Don't judge a protein by its length The Human Genome Project yielded a blueprint for the human genome. Even after the DNA code was cracked, understand- ing what it meant was the next challenge. Scientists first set out to identify protein-coding genes. They started with some basic rules for defining protein-coding genes, which included a specific starting signal, a long sequence of code, and a final stop sign. Researchers verified that the sequence between the two signs encoded a protein. The protein-coding segments between the start and stop signs are called an open reading frame (ORF ), and scientists initially thought only ORFs longer than 100 bases would make proteins. Herein lies the microprotein conundrum. Microproteins are short proteins made from short ORFs. Scientists originally thought only long ORFs encoded proteins, but this missed many microproteins. Scientists needed new molecular tools to figure out which ORF regions were being made into proteins. Several of the molecular techniques developed were instrumental in identifying microproteins that were only first discovered in the 1990s. These advancements led to the finding of nearly 7,000 microproteins in humans alone. As with the Human Genome Project, the work in this field has now shifted to determining the function of this class of proteins. Understanding how these
microproteins work could lead to the development of new drugs or even modifications of the proteins themselves, potentially offering significant benefits for treating diseases. Scientists have already discovered some amazing things these microproteins can do. For example, one microprotein helps bacteria hide from antibiotics, while another is involved with how bacteria communicate with each other. Others might control how cells use energy. n
REFERENCE: Arnaud, C., Exploring the world of microproteins. Chemical and Engineering News (2023) 101 (19) and figure NHGRI. https://cen.acs.org/ biological-chemistry/proteomics/Exploring-world-microproteins/101/i19
Mystery prints Human fingerprints are unique and complex ridges of arches, loops, and whorls that are consistent throughout life and can be used to identify individuals. There have been several theories that fingerprints may develop from skin wrinkles or that the ridges follow the blood vessels. Until now, the mechanism that creates fingerprints was a mystery. The arches, loops, and whorls that form on the fingertips start defining in the womb because of signaling between three molecules. WNT tells cells to form the ridges and produces the second molecule, EDAR, which helps create more cells. The third molecule, BMP, prevents EDAR from making more ridges. This complex set of interacting signals forms a Turing pattern system that propagates outwards. As ridges develop, they form sets of waves that start to spread from three initiation sites: the center of the fingertip, under the nail, and the crease near the knuckle. With slight variations in timing, as they make their way to the middle of the fingertip, these interactions form the unique fingerprint pattern. Researchers used mice to examine how these molecules interact. Mice don’t have fingerprints, but the striped ridges
The Unknome Despite much progress, we still don’t know everything about the human genome. A new database aims to catalog human genes and proteins we know little about. The Unknome – the words unknown and genome – has nearly 2 million proteins
and assigns them a “knownness” score based on how much we understand about the genes. The proteins are grouped into families with over 3,000 groups; 805 contain a human protein with a score of zero. Cell biologists used the database to study the genes shared between fruit flies and humans with very low knownness scores. Of the 260 genes with low scores, when compared to fruit flies, 60 homologs of the unknown genes were essential for life, and others were important for growth, development, movement, and resilience against stress. How they function in humans is a mystery despite their importance in fruit flies. As for cell biologists, the next step is to use the database to partner with others for a large-scale study of these unknown proteins. With the many mysterious genes and proteins out there, this new database can help researchers prioritize and learn more about these unknowns. The hope is that the Unknome database will shrink over time. n REFERENCE: Rocha, J. J., et al. Functional unknomics: Systemative screening of conserved genes of unknown function. PLoS Biol (2023) 21(8): e3002222. doi.org/10.1371/journal.pbio.3002222
on the skin of their toes are comparable to human prints. Increasing EDAR led to thick and spaced-out ridges, and decreasing EDAR led to spots. Mouse prints are too tiny to see the shapes found on human fingerprints, so researchers used computer models to sim- ulate the effects seen in the mouse model and could reproduce and create a human fingerprint. n
REFERENCE: Glover, James D. et al. The developmental basis of fingerprint pattern formation and variation (2023) Cell , Volume 186, Issue 5, 940 - 956.e20. doi.org/10.1016/j.cell.2023.01.015
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