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There are approximately 22,000 genes in our genome. Genes are fragments of the DNA sequence generally described as the basic units of heredity. Genes give rise to proteins, which play specific functional roles within cells and collectively determine the physiological state of our organism.
However, not all genes are equally relevant for life viability. Indeed, the inactivation of some of them does not really have consequences in human health. In 2012, a study led by Daniel G. MacArthur of the Wellcome Trust Sanger Institute in England, published in the journal Science, estimated from a sample of 185 healthy individuals, that on average each of us has approximately a hundred of genes inactivated in at least one of its two copies by diverse genetic variants, with about 20 of them disrupted in their two copies.
Genes on the road to fossilization
Two Imagine laboratories, that codirected by Laurent Abel* and Jean-Laurent Casanova**, and that of Antonio Rausell***, wanted to find out more about which are those genes that are fully inactivated by genetic variants in a large fraction of humans, using this time as a reference more than 120,000 individuals from the Genome Aggregation Database (gnomAD) representative of 5 major human populations (Africans, including African Americans, East Asians, South Asians, Europeans, and Admixed Latino Americans).
"We found 166 genes for which more than 1% of individuals in at least one of the 5 populations evaluated carry a genetic variant inactivating both of their copies”, Laurent Abel points out.
Not surprisingly, most of the genes that can be knocked out without impacting an indivual’s health are involved in non-essential cellular functions. They participate in molecular mechanisms that could have been relevant to our ancestors or other species but are no longer necessary for human survival. For instance, 41 out of the 166 genes identified are olfactory receptors. However, others genes can be inactivated without major consequences because of genetic redundancy. Here, the function of those genes may actually be still relevant but is already carried out by other genes. Under such scenario, some genes may no longer be subject to negative selective pressures (which naturally remove damaging genetic variants from the population) and could ultimately become non-functional genes called “pseudogenes” or “fossil genes”.
When the loss of a gene is actually beneficial for human survival
Alternatively, some of the inactivating genetic variants could also lead to an advantage for the individuals that carry them. Indeed, loss-of-function variants involving 8 genes were identified in the study as undergoing positive selection, i.e. when genetic variants conferring a beneficial effect for survival are naturally retained in the population. Among them, authors found a variant inactivating the FUT2 gene which was known to confer resistance to intestinal viruses, and a loss-of-function variant in APOL3 involved in resistance to parasitic infections. “The identification of variants that are retained in the recent human history because of a gene inactivation conferring beneficial effects for survival, may pinpoint drug targets for the treatment of the associated diseases in non-carrier individuals”, explains Antonio Rausell.
The study contributes to the identification of human genes whose functions are nowadays redundant or even advantageous for human survival. The identification of these benign variants is also useful when analysing the genome, in order to exclude them as potential causes of disease.
*Laurent Abel is an Inserm director of research, co-director with Jean-Laurent Casanova of the Laboratory of Human Genetics of Infectious Diseases, an Inserm international laboratory organized in two branches, one at the Imagine Institute in Paris and the other at the Rockefeller University in New York.
**Jean-Laurent Casanova is a professor at the University of Paris/Hôpital Necker-Enfants malades AP-HP and at Rockefeller University in New York, a Howard Hughes Medical Institute investigator, and co-director of the Laboratory of Human Genetics of Infectious Diseases.
*** Antonio Rausell is an Inserm researcher and director of the Clinical Bioinformatics Laboratory at the Imagine Institute.
Des gènes silencieux mais utiles malgré tout
Cependant, certains de ces gènes inactivés peuvent procurer un avantage pour les individus qui les portent. Dans l’étude, 8 d’entre eux présentait des signes de sélection positive. Ainsi le variant perte de fonction touchant le gène FUT2 confère une résistance aux virus intestinaux, et celui d’APOL3 est impliquée dans la résistance aux infections parasitaires. « L’identification de ces variants sélectionnés positivement du fait de l’effet bénéfique pour la survie de l’inactivation du gène correspondant, peut permettre de définir des cibles thérapeutiques potentielles pour les pathologies associées chez les individus non porteurs de ces variants, » explique Antonio Rausell.
Cette étude permet donc l'identification de gènes dont les fonctions sont désormais redondantes, voire même avantageuses, pour la survie humaine. L’identification de ces variants « bénins » est également utile lors de l'analyse du génome chez des patients, afin de les exclure comme causes potentielles de maladie.
*Laurent Abel est directeur de recherche à l’Inserm, co-directeur avec Jean-Laurent Casanova du Laboratoire de génétique humaine des maladies infectieuses, laboratoire international de l’Inserm organisé en deux branches, l’une à l’Institut Imagine à Paris et l’autre à l’Université Rockefeller à New York.
**Jean-Laurent Casanova est professeur à l’Université de Paris/Hôpital Necker-Enfants malades AP-HP et à l’Université Rockefeller à New York, investigateur au Howard Hughes Medical Institute, et co-directeur du Laboratoire de génétique humaine des maladies infectieuses.
*** Antonio Rausell est chercheur Inserm et directeur du laboratoire de Bioinformatique Clinique à l’Institut Imagine
