title: Gene age predicts the strength of purifying selection acting on gene expression variation in humans.
abstract: Gene expression levels can be subject to selection. We hypothesized that the age of gene origin is associated with expression constraints, given that it affects the level of gene integration into the functional cellular environment. By studying the genetic variation affecting gene expression levels (cis expression quantitative trait loci [cis-eQTLs]) and protein levels (cis protein QTLs [cis-pQTLs]), we determined that young, primate-specific genes are enriched in cis-eQTLs and cis-pQTLs. Compared to cis-eQTLs of old genes originating before the zebrafish divergence, cis-eQTLs of young genes have a higher effect size, are located closer to the transcription start site, are more significant, and tend to influence genes in multiple tissues and populations. These results suggest that the expression constraint of each gene increases throughout its lifespan. We also detected a positive correlation between expression constraints (approximated by cis-eQTL properties) and coding constraints (approximated by Ka/Ks) and observed that this correlation might be driven by gene age. To uncover factors associated with the increase in gene-age-related expression constraints, we demonstrated that gene connectivity, gene involvement in complex regulatory networks, gene haploinsufficiency, and the strength of posttranscriptional regulation increase with gene age. We also observed an increase in heritability of gene expression levels with age, implying a reduction of the environmental component. In summary, we show that gene age shapes key gene properties during evolution and is therefore an important component of genome function.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Institute for Information Transmission Problems (Kharkevich Institute), Russian Academy of Sciences, Moscow 127994, Russia. Electronic address: konstantin.popadin@unige.ch.
authors.forename: Konstantin Y
authors.initials: KY
authors.lastname: Popadin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez-Arcelus
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland; New York Genome Center, Avenue of the Americas 101, New York, NY 10013, USA; Department of Systems Biology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Lappalainen
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Steinberg
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Nikolaev
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Lukowski
authors.affiliation: Institute for Information Transmission Problems (Kharkevich Institute), Russian Academy of Sciences, Moscow 127994, Russia; School of Bioengineering and Bioinformatics, Moscow State University, Vorobievy Gory 1-73, Moscow 119992, Russia.
authors.forename: Georgii A
authors.initials: GA
authors.lastname: Bazykin
authors.affiliation: Institute for Information Transmission Problems (Kharkevich Institute), Russian Academy of Sciences, Moscow 127994, Russia; School of Bioengineering and Bioinformatics, Moscow State University, Vorobievy Gory 1-73, Moscow 119992, Russia.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Seplyarskiy
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ioannidis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Evgeny M
authors.initials: EM
authors.lastname: Zdobnov
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000367:Age Factors; D002460:Cell Line; D005260:Female; D005312:Fetal Blood; D005347:Fibroblasts; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D016678:Genome / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics*; D024363:Transcription Initiation Site; D014470:Umbilical Cord
chemical_list: D011506:Proteins