Harvard Associate Prof. Shamil Sunyaev on protein evolution model, human disease mutations, and the help of different vertebrate species for human genetic research
What purposes can DNA sequencing serve? What can happen after injecting human mRNA in zebrafish? Associate Professor of Medicine at Harvard Medical School Shamil Sunyaev speaks on tools that allow us to find the most important genetic changes.
The idea is that long-term evolution may help explaining variations in humans now. Currently, we have access to genomes of 44 vertebrate species. And building a model of evolution at this specific position in DNA, we can ask the questions, whether this human mutation fits this pattern that we observed in long-term evolution. Changes that are happening between different vertebrate species, either they are predictive or you would anticipate this change in the human population, or you would not anticipate this change.
This can be complemented also by looking at the level of structure of molecules, when they are available. If you look at structures and you can compute change in free energy for specific proteins, free energy of folding, how stable is native conformation of this protein — this also can be informative. There are several lens of evidence that this method works, in statistical sense. One is that we can take very large set of human disease mutation and set of variants which are common in the population and to the best of our knowledge don’t do any harm. And we can separate them statistically. However, not very well, with accuracy of about 80%. We can also look at the population and correlate these functional changes with statistical test of natural selection and see that these variants are primarily under pressure of natural selection.
One possibility is to look at situation in a model organism, for example in zebrafish. Some labs do the following experiment: they find a gene in zebrafish, in specific model organism being a small fish species, find a gene which we call orthologues of human genes, gene which is probably, roughly speaking, is the same gene as in humans. And they can knock down function of these gene, and see what happens with the fish. If something happens, they know that this gene is important.