Scientists have historically examined genetic variations within species to better understand what causes biological diversity on Earth. However, this only offers a portion of the picture. A species’ characteristics are produced by both the proteins that its genes code for and the genes themselves. Thus, just as important as understanding differences between genomes is understanding differences between proteomes, or all of the proteins that can be expressed.
In a recent study, Yale researchers compared the proteomes of skin cells from 11 different mammals. They say that this comparison will help us learn more about the molecular processes that make up biodiversity and how these processes have changed over time.
While many proteins exhibit similar variation between and within species, they discovered that some proteins exhibit greater variation between species, offering hints as to which proteins may have played a more significant role in the evolution of mammals. The research might also shed some light on why some species are more cancer-resistant than others.
Science Advances published their findings on September 9.
According to Günter Wagner, the Alison Richard Professor Emeritus of Ecology and Evolutionary Biology, “you may want to know how species behave, develop, and look different in order to understand biological diversity, along with knowing how DNA is different across species.”
Yansheng Liu, an assistant professor of pharmacology at Yale School of Medicine, thinks that protein levels are more important than DNA when it comes to how a species looks, acts, and grows.
However, the lack of large-scale analysis technology has made it challenging to compare protein amounts across species. But thanks to Liu’s application of a technique called data-independent acquisition mass spectrometry, scientists can now carry out this kind of work.
According to Wagner, the ability to work at this higher, more functionally relevant level is the result of a conceptual and technical breakthrough.
At Yale’s West Campus, Liu is a member of the Yale Cancer Biology Institute, and Wagner is a member of the Yale Systems Biology Institute. Their collaboration started there, at a cancer systems biology symposium they both attended.
For the study, the amount of each protein found in the skin cells of rabbits, rats, monkeys, humans, sheep, cows, pigs, dogs, cats, horses, and opossums was measured.
They discovered that the analysis offered details that weren’t available from other methods. Since mRNA is only an indirect indicator of protein abundance, previous studies that looked at differences in mRNA—the genetic material used to make proteins—found that measuring proteins provided additional information that couldn’t be captured by doing so.
The instructions for making a protein are encoded on an mRNA strand. Furthermore, Liu added, proteins can interact with one another and perform as a group in addition to having a specific function as single proteins. That information won’t be revealed by simply looking at mRNA.
“We discovered that the protein relationship to mRNA is very low, especially for certain protein classes,” said Liu. That implies that relying solely on the mRNA profile would be false.
The team then examined protein variation within and between species, as well as between individuals within the same species, and discovered that, for the majority of proteins, levels that varied more between individuals and species also varied more between species. However, some proteins deviated from this pattern. For instance, proteins involved in cell division and RNA metabolism varied more between species than within individuals of a single species (humans, in this case). Researchers say this shows that these functions have a big effect on how mammals have changed over time.
According to Wagner, “inter-individual versus inter-species differences are very interesting from an evolutionary point of view.” We can predict the potential for evolution by comparing the two to get a sense of how much variation is tolerated within a species.
Finally, the scientists examined protein-removal mechanisms in various species. They found that one of the two main ways cells get rid of proteins was the same in all mammals, but the other way was very different between species of mammals.
According to Wagner, the rate at which a cell can change its state is governed by protein turnover. If the cell gets a new signal, it has to make new proteins instead of the ones it needed for the previous state.
Additionally, a cell’s rate of state change may have an impact on cancer.
“Nearby cancer cells can affect healthy cells,” said Wagner. It will be crucial to determine whether protein turnover rates are associated with how responsive cells are to tumor cell influences. Perhaps cancer-resistant species, like those with hooves like cows and pigs, have cells that are less capable of changing their state and less vulnerable to signals from cancer cells.”
This work’s potential applications include understanding cancer vulnerability, according to the researchers. For instance, Liu says they can start relating any other traits that differ between species with protein differences.
When other molecules bind to proteins and activate or deactivate them, proteins are subject to chemical modifications. And because these modifications have a significant impact on how proteins function, they also contribute to traits that vary between and within species. One type of modification, phosphorylation, was examined in this study, and the researchers discovered that variations in phosphorylation levels were, for the most part, unrelated to variations in protein abundance, adding yet another layer of comprehension about what motivates biodiversity. In their upcoming work, the researchers will keep evaluating additional modifications.
Liu added that biological differences between species and individuals are what shape biological diversity on Earth, and that this will “provide a more complete picture.” We will learn more about biodiversity at the molecular level as a result of measuring the variations in proteins and proteins that have been modified between species.
