A genetic macro-study carried out with more than 2,500 families affected by autism, has made it possible to determine that the most unknown fraction of the human genome is involved in the origin of this disorder and that the alterations that occur in it are inherited, mainly by the father, publishes Science.
The study was led by Jonathan Sebat, from the Department of Psychiatry of the University of California San Diego (USA) and four Spanish centers: the Pompeu Fabra University, the University of Barcelona, and the San Joan de Déu hospitals, and the Mútua de Terrassa University Hospital, both of Barcelona.
The work, the result of a complex international multidisciplinary collaboration, is based on the analysis of the complete genome of some 3,000 people from nearly a thousand families with at least one member affected by Autistic Spectrum Disorder (ASD), together with their parents and siblings. , and its results have been validated with an additional 1,700 families.
“The objective of the work is to contribute to complete the genetic landscape of autism,” because this disorder (with a genetic component greater than 70%) is “very complex,” explained Bru Cormand, researcher at the University of Barcelona, Center for Biomedical Research in the Network of Rare Diseases (CIBERER) and co-author of the study.
And, although in the last decade at least one hundred genes have been identified that cause ASD, “none of them explains more than 1% of the cases”, so there must be other alterations still unknown of the genetic material that lead to this disorder.
One of the most relevant aspects of the work is precisely how the research has been done.
And, until recently, the massive sequencing techniques did not offer a detailed map of the entire genome: they only allowed to see the exome, that is, the fraction of the genome that codes for proteins, which are a minimum part of the genome (the 1% of DNA).
However, this work has been carried out with the Whole-genome Sequencing (WGS) technique, which allows us to explore the rest of the genome, the most unknown part, the so-called ‘junk’ genome that “we know is there, but of which we do not know well his function “, detailed to Efe Roser Corominas, scientist of the Pompeu Fabra and coauthor of the study.
Until now, almost all research has focused on point mutations of the exome, but this work has analyzed alterations produced in other regions of the genome and in which changes in intergenic regions (such as some small duplications or loss of genetic material) have repercussions in many Other segments of the genome, because they affect elements that regulate the expression of genes, the researchers detail.
The study – carried out in an initial phase with a thousand families and a subsequent one of validation of the results – determined that these alterations (or structural variants) affecting large segments of the genome are present in about 11% of patients, when Until now they were considered responsible for less than 2% of the cases. “It’s an important step,” Cormand stressed.
But, in addition, the study detected an important sex bias in the transmission of these alterations.
“Sex is important in ASD because the proportion of affected is four children for each girl, there must be something to explain it.”
And although “it is still unclear, we have now seen that when the alterations directly affect genes are transmitted predominantly by the mother, while when they affect regions that regulate the function of the genes, they come predominantly from the father,” said the researcher.
The finding has been a “surprise” because until now it was thought that the variants that were inherited and conferred susceptibility to autism came mainly from the maternal route but now we have seen that it is not always the case and that the transmission of these structural variants in these regulatory regions come from the father, “added Corominas.
“The work is relevant because it has allowed us to analyze the most unknown part of the genome and identify variants that had not been seen until now and also discover that there is a part of the genetic risk of having ASD that is inherited and that comes predominantly from the father. which shows us that the inheritance of autism is more complex than previously thought, “he concluded. EFE