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4 Understanding the Contributions of Non-Protein-Coding DNA to Phenotype
Pages 39-52

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From page 39...
... The first speaker was Felicity Jones of the Friedrich Miescher Laboratory of the Max Planck Society, who described her studies of the role played by non-coding portions of the genome in adaptation by stickleback fish. Scott Edwards of Harvard University spoke about his research on the evolution of non-coding regulatory sequences in various taxa of birds that have lost the ability to fly through evolutionary changes.
From page 40...
... For example, the freshwater sticklebacks have lost many or all of their bony lateral plates, which the marine ancestor still retains, and that adaptation in the freshwater fish occurred independently many different times. This makes it possible to study the mechanisms behind these parallel evolutionary changes.
From page 41...
... Her team learned a lot from this initial work. First, there are many places across the genome where freshwater and marine fish have evolved divergent blocks of DNA, such that "any freshwater fish collected in the wild will be carrying the freshwater allele in as many as 81 different locations around the genome." Furthermore, marine versus freshwater adaptation is highly polygenic.
From page 42...
... "And," she added, "we've been doing a whole bunch of transgenic assays to develop what we see." The result has been a tremendous amount of data to analyze to identify regions that differ between the marine and freshwater ecotypes and thus to identify putatively divergent regulatory elements. Once the candidates have been identified, Jones and her team perform functional assays to test whether the blocks of DNA actually contain regulatory elements.
From page 43...
... Although flightless birds are rather unwieldy as models, Edwards said, they are powerful in what they allow people to learn about the genetics of adaptive evolution -- and, in particular, about the convergent changes in non-coding regulatory sequences that occurred in various taxa of birds that independently lost the ability to fly. Edwards and his team are interested in various phenotypes mainly involving changes related to loss of flight.
From page 44...
... As an example, he mentioned a 250-base-pair, non-coding element that was highly conserved throughout the lineages of birds that maintained the ability to fly but that was visibly increasing in rate of appearance among some of the flightless lineages. The identification of such elements can be formalized in a statistical model, he said, explaining that two of the key things needed in this approach to functional genomics are statistical models that link genotype to phenotype and other models that detect changes in rate -- and potentially changes in function -- in non-coding elements (Hu et al., 2019)
From page 45...
... They found that the versions from the two flying species were able to successfully drive gene expression in the developing forelimb of chickens, while the version from the rhea was not. This showed that at least one of the elements identified by their method has functional consequences for gene expression.
From page 46...
... Spitz began by noting, as other speakers had, that gene expression is shaped to a substantial degree by cis-regulatory elements, DNA regions that are near genes but separate from the core promoter regions. What is seen in many animals, especially vertebrates, is that gene regulation is extremely modular, and is frequently related to a large series of regulatory elements around the gene.
From page 47...
... What researchers have found is that the genome is organized in distinct and nested structures of different sizes. The structure looks different at different scales, but if one examines the structure at the scale of a few hundred thousand bases, what appears are a series of self-interacting domains called topologically associated domains, or TADs.
From page 48...
... The first is based on the underlying chromatin structure and segregates regions into active and inactive compartments. "That's a system which will ensure maintenance of activities," he said.
From page 49...
... Spitz responded by saying that there is no consensus in the community related to how accurately interactions between genes and enhancers can be measured, and researchers are just starting to address this question with new tools such as live imaging, high-resolution microscopy, and functional strategies. In relation to topological domains, he pointed out the fact that some loci provide a clear picture of what interaction is happening, while others show interactions that are diffuse and difficult to define.
From page 50...
... "So there might be many ways to kill gene expression, but few ways to evolve or gain gene expression." Edwards answered the first part of Kocher's question by saying that for non-coding elements it is often not clear whether adaptive evolution is driving changes or if it is just degradation of the element. Concerning the second part of the question related to master regulators, he said that it should be possible to combine something like ATAC-seq data and gene expression data to learn more about where the regulators are for gene expression.
From page 51...
... While Spitz had not, Jones reiterated that a number of trans-acting elements had been discovered during experiments where they are doing standard quantitative trait locus mapping with chromatin profiles as a phenotype. "We're at the point of trying to identify whether they are these known complexes," she noted.


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