The role of the interactome in the maintenance of deleterious variability in human populations
Abstract Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes...
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| Format: | Article |
| Language: | English |
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Springer Nature
2014-09-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20145222 |
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| author | Luz Garcia‐Alonso Jorge Jiménez‐Almazán Jose Carbonell‐Caballero Alicia Vela‐Boza Javier Santoyo‐López Guillermo Antiñolo Joaquin Dopazo |
| author_facet | Luz Garcia‐Alonso Jorge Jiménez‐Almazán Jose Carbonell‐Caballero Alicia Vela‐Boza Javier Santoyo‐López Guillermo Antiñolo Joaquin Dopazo |
| author_sort | Luz Garcia‐Alonso |
| collection | DOAJ |
| description | Abstract Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins. |
| first_indexed | 2024-03-07T16:43:57Z |
| format | Article |
| id | doaj.art-0aa3068e96ee438b8a85b370a6acd041 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T16:43:57Z |
| publishDate | 2014-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-0aa3068e96ee438b8a85b370a6acd0412024-03-03T07:05:21ZengSpringer NatureMolecular Systems Biology1744-42922014-09-01109n/an/a10.15252/msb.20145222The role of the interactome in the maintenance of deleterious variability in human populationsLuz Garcia‐Alonso0Jorge Jiménez‐Almazán1Jose Carbonell‐Caballero2Alicia Vela‐Boza3Javier Santoyo‐López4Guillermo Antiñolo5Joaquin Dopazo6Computational Genomics Department Centro de Investigación Príncipe Felipe (CIPF) Valencia SpainComputational Genomics Department Centro de Investigación Príncipe Felipe (CIPF) Valencia SpainComputational Genomics Department Centro de Investigación Príncipe Felipe (CIPF) Valencia SpainMedical Genome Project Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville SpainMedical Genome Project Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville SpainMedical Genome Project Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville SpainComputational Genomics Department Centro de Investigación Príncipe Felipe (CIPF) Valencia SpainAbstract Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.https://doi.org/10.15252/msb.20145222exome sequencinginteractomemutational loadnetwork analysisrobustness |
| spellingShingle | Luz Garcia‐Alonso Jorge Jiménez‐Almazán Jose Carbonell‐Caballero Alicia Vela‐Boza Javier Santoyo‐López Guillermo Antiñolo Joaquin Dopazo The role of the interactome in the maintenance of deleterious variability in human populations Molecular Systems Biology exome sequencing interactome mutational load network analysis robustness |
| title | The role of the interactome in the maintenance of deleterious variability in human populations |
| title_full | The role of the interactome in the maintenance of deleterious variability in human populations |
| title_fullStr | The role of the interactome in the maintenance of deleterious variability in human populations |
| title_full_unstemmed | The role of the interactome in the maintenance of deleterious variability in human populations |
| title_short | The role of the interactome in the maintenance of deleterious variability in human populations |
| title_sort | role of the interactome in the maintenance of deleterious variability in human populations |
| topic | exome sequencing interactome mutational load network analysis robustness |
| url | https://doi.org/10.15252/msb.20145222 |
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