All humans were at some point a single omnipotent cell of 0.1 millimeters, the result of the union of an egg from their mother and a sperm from their father. Within that single cell was already an exclusive and amazing text: the genome, more than 3,000 million chemical letters instructing you to reproduce and become a human with 30 trillion cells. It is what the American geneticist Francis Collins, a staunch Christian and former director of the Human Genome Project, calls “the language of God.” But there is another god above this supposed god. Almost all of a person’s cells have the same original instruction manual, but some read a few pages and become neurons in the brain, and others read other passages and generate cells of muscle, heart, or some other organ. . An international consortium this Thursday presents the most complete map of this other god who decides how to read the book of life: the epigenome.
According to Roderic Guigó, a researcher at the Center for Genomic Regulation (CRG) in Barcelona and co-author of the study, scientists examined the genetic material of four deceased organ donors, two women and two men. “This is the most complete personal map of the human epigenome,” says Guigó. The breakthrough opens a new door to medicine. The epigenome are chemical compounds attached to the genome — the famous DNA — as if they were highlighters and bookmarks, pointing to the parts of the book that need to be read. The process is fundamental for the normal development of a fertilized egg cell, but also for the occurrence of diseases such as cancer.
Another international consortium published a reference map of the epigenome back in 2015, but Guigó points out that it was built on top of the human reference genome, an “archetypal” text that doesn’t correspond to any specific individual but is a mixture of scraps of DNA from a dozen Persons. The new study, published in the journal Cell, shows personalized maps of 30 different tissues – lungs, heart, liver – of the four who died. “For the first time, we can study epigenomic variation both across tissues and across individuals,” says Guigó.
If DNA is a book, the epigenome is the person reading that book, a sort of librarian who decides which parts to read.
Beatrice Borsari, biotechnologist
A cell’s DNA is organized into 23 pairs of packages called chromosomes. In each pair, one chromosome is inherited from the mother and one from the father. Italian biotechnologist Beatrice Borsari points out that it is the first time that both the genome and the epigenome of the two copies of each chromosome have been studied with this level of detail. “If DNA is a book, the epigenome is the person reading this book, a kind of librarian who decides which parts to read,” explains Borsari, who received her doctorate from the CRG and is now a researcher at Yale University (USA). ), another institution of the consortium.
A person’s genome contains about 4.5 million mutations compared to the reference published two decades ago. Most are harmless, but some can be harmful or even beneficial. The new epigenomic maps shed light on the effect of these mutations, including whether they were inherited from the mother or father. “We were able to analyze the mutations in the genome of certain individuals, how they can change their epigenome and thus change the way these instructions are read in different tissues,” explains Borsari. In the world of DNA, errors in the book also cause the transformation of the librarian who reads it.
The American geneticist Thomas Gingeras, one of the leaders of the consortium, sees this as a decisive step towards personalized medicine. “For a long time it was clear that the ideal would be to obtain the sequence of the whole world’s genome and analyze the effects of the variations as a basis for diagnosis and the selection of a treatment. Medicine is aimed at this goal. And this is an attempt to provide a paradigm for it,” Cold Spring Harbor Laboratory’s Gingeras defended in a statement.
These are the bases on which we can now build specific research that tells us about cancer risk
Manel Esteller, geneticist
The authors created a catalog of millions of mutations called EN-TEx, which they used to train an algorithm that predicts the impact of these changes on the risk of developing disease. Beatrice Borsari cites the example of primary ciliary dyskinesia, a rare respiratory disease that affects the lungs and hearing. “It’s a problematic disease and we’ve been able to study some mutations that occur in a gene and understand how they change the epigenome. If I have a patient with these mutations, I can make predictions,” says Borsari.
The biotechnologist highlights another benefit of her map: the ability to study the effects of mutations on hard-to-reach organs of a living person, such as the heart or brain. The authors used machine learning techniques to be able to recognize patterns and draw conclusions from a simple blood test.
Geneticist Manel Esteller welcomes the new work, which he did not collaborate on. “They are the bases on which specific research can be built that tells us about the risk of cancer, susceptibility to serious infections or factors related to healthy aging,” says Esteller, director of the Josep Carreras Leukemia Research Institute in Badalona (Barcelona ). .
The authors acknowledge the limitations of their study: They only examined the epigenome of four individuals, and all had European ancestry and lived in the United States. “We would like to add more people to have more statistical power and include people from different ethnicities. A mutation can be common in white people but rare in other groups,” explains Borsari.
The Italian scientist is already working on the next phase of medicine in her laboratory at Yale University. “Knowing about mutations in the genome is very important, but knowing how they change the epigenome is another level that takes us much further. If the DNA is my book and the epigenome is the person reading the book, the next step is to figure out what happens after you read the book. How does the cell change?” he asks himself.
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