MOOC How Genomes Evolved- 5.3. Epigenetic changes in the human lineage (Universidad de Navarra)

I hope that throughout this course I have made it sufficiently clear that having a genome with a particular sequence is not the end of the story. The information contained in the genome is read by the cell when genes are transcribed, expressed, and it is the regulation of gene expression, the finely regulated turning on and off of specific genes at specific times and tissues, that enables organisms to develop and to keep functioning. Today, looking at the genome with new technologies, we can find some marks, beyond the nucleotide sequence, that tell us whether this or that gene is active or silent. These marks are called epigenetic modifications, because they don’t change the sequence itself but still affect how genomic information is decoded. There are two major types of epigenetic modifications: the methylation of DNA, which usually turns down gene activity, and the chemical modification of histones, histones are the proteins around which the DNA is wound inside the nucleus of the cells. Histone modifications can be either activating or repressive of gene expression. So we can search the genome for these marks and depending on the combination of epigenetic modifications that we find at particular genes, the sort of code of DNA and histone changes at that point, we know whether that gene is active or not. And we can do this in different cells or tissues, so we will know whether that gene is active in brain but silent in liver, for instance. But we can also compare the genomes of different species, so we can go a step further and ask: are there epigenetic modifications that are unique to humans? Are there any genes related to brain development that have all the active marks in humans but not in other great apes? As you can imagine, such changes could lead to important phenotypic changes (like the size or the internal structure of the brain) without substantial changes in the sequence of the genes. Well, recently we have just started to have some answers to these questions. Over the last couple of years, scientists have analysed the patterns of DNA methylation in humans and in great apes (chimpanzee, gorilla and orang-utan) and they found almost 200 genes with epigenetic marks that are unique to humans, so those genes are working differently in us than in great apes even though their sequence is identical. And then another study analysed a histone epigenetic mark, which is typical of active genes in the genomes of humans of various ages as well as in the genomes of other primates. What is interesting about this work is that the genomes were obtained from cells in a region of the brain known as the prefrontal cortex, which is very important in cognition and is associated with the evolution of the primate brain. So they looked for active chromatin marks in genomes coming from this particular part of the brain in several species. And they found hundreds of short regions with histone modifications that are only present in humans (as compared to chimpanzees and macaques), including 33 sites which activate genes only in the human brain. And what is really striking is that many of those genes are implicated in brain development and in the susceptibility to psychiatric disease in humans. And what’s more, the authors of this work also looked at the position occupied by these genes within the nucleus of the cells in the prefrontal cortex, and they found that they tend to cluster together, even though they are separated by millions of nucleotides. This suggests that they might act in concert, perhaps to promote the development of that region of the brain, only in humans but not in other great apes in which the prefrontal cortex is not so well developed. So this is yet another example of a genetic change (epigenetic change in this case), that might have contributed to the evolution of the human brain.

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