Experts discover oldest DNA regulatory region known to date in vertebrates and invertebrates

The article was written by Jordi Garcia-Fernández, Ignacio Maeso, Manuel Irimia and Salvatore D'Aniello, from the Department of Genetics and the Institute of Biomedicine of the University of Barcelona (IBUB), and additional authors from research teams led by José Luis Gómez-Skarmeta (Andalusian Centre for Developmental Biology, CSIC) and Eric H. Davidson (California Institute of Technology, United States).

How can the genes of an organism be expressed in such a way as to create such strongly differentiated cell types? Regulation of gene expression is a key process in the specific activation of different gene types and results from a delicate balance in the genetic machinery of the cell. A first level of control consists of short sequences of DNA, located close to the genes, which act as expression regulatory regions.

The study published in PNAS was carried out with phylogenetically distant species, in which the ancestral regulatory sequence was found: specifically, with vertebrates (humans and zebra fish) and invertebrates (cnidarians, echinoderms, cephalochordates and hemichordates). One of the mainstays of the article is the work carried out to sequence the amphioxus genome (Nature, 2008), contributed to by a UB research team directed by Jordi Garcia-Fernández, whose study of noncoding sequences in the amphioxus genome is generating data that can be used to better understand the biological evolution of the three groups of chordates (tunicates, lancelets and craniates), the transition between invertebrates and vertebrates and the origin of the human genome.

Maintaining sequence and function for 1,000 million years

As professor Jordi Garcia-Fernández explains, "The study reveals the first evidence of a noncoding sequence region deeply evolutionarily conserved for more than 1,000 million years, which has maintained its activity in the control of neurogenesis throughout the evolution of metazoans." The sequence is a small DNA fragment with a structure that facilitates the binding of transcription factors in a specific order, acting as a cis-regulatory module of soxB2 expression, a gene family with a role in controlling the development of the nervous system.

This DNA fragment displays exceptionally high homology and a largely conserved function in vertebrate and invertebrate genomes. As Garcia-Fernández notes, "A surprising outcome of the study was the identification of a genetic sequence highly conserved over thousands of years in such different organisms, with an equally highly conserved pattern of biological functions. The results from the Drosophila melanogaster model are also particularly impressive. Although until now this noncoding region had not been identified in the genome, we have found that once it is inserted it can direct gene regulatory machinery in the development of the brain and occipital lobe."

Genes: more functions, greater complexity

The results of the study published in PNAS indicate a phenomenon of growing evolutionary importance: gene co-option. "The complexity of living beings," says Garcia-Fernández, "was not produced simply by the appearance of new genes. A gene can be co-opted; that is, it can be used for a new function, and in many cases this phenomenon has paved the way for evolutionary innovation. Before it was thought that the most complex organisms derived their complexity from the possession of a larger number of genes, but this is not the case. They are complex because the same genes have been co-opted to acquire new functions."

Many of the genetic alterations associated with human diseases are found in noncoding regions of the genome. One of the major challenges in comparative genomics will be to detect mutations in regulatory areas, which are fundamental in the control of gene expression. Garcia-Fernández explains that, "Traditionally, genetics has focused on the study of coding regions, but around 97% of the genome does not encode protein sequences." As such, he concludes that, "Since everything seems to suggest that evolution came about above all as a result of changes in cis-regulatory regions, the study of areas of the genome with a regulatory function looks set to have more and more impact on the world of genetics and molecular biology."