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Gene co-expression network connectivity is an important determinant of selective constraint.

ABSTRACT: While several studies have investigated general properties of the genetic architecture of natural variation in gene expression, few of these have considered natural, outbreeding populations. In parallel, systems biology has established that a general feature of biological networks is that they are scale-free, rendering them buffered against random mutations. To date, few studies have attempted to examine the relationship between the selective processes acting to maintain natural variation of gene expression and the associated co-expression network structure. Here we utilised RNA-Sequencing to assay gene expression in winter buds undergoing bud flush in a natural population of Populus tremula, an outbreeding forest tree species. We performed expression Quantitative Trait Locus (eQTL) mapping and identified 164,290 significant eQTLs associating 6,241 unique genes (eGenes) with 147,419 unique SNPs (eSNPs). We found approximately four times as many local as distant eQTLs, with local eQTLs having significantly higher effect sizes. eQTLs were primarily located in regulatory regions of genes (UTRs or flanking regions), regardless of whether they were local or distant. We used the gene expression data to infer a co-expression network and investigated the relationship between network topology, the genetic architecture of gene expression and signatures of selection. Within the co-expression network, eGenes were underrepresented in network module cores (hubs) and overrepresented in the periphery of the network, with a negative correlation between eQTL effect size and network connectivity. We additionally found that module core genes have experienced stronger selective constraint on coding and non-coding sequence, with connectivity associated with signatures of selection. Our integrated genetics and genomics results suggest that purifying selection is the primary mechanism underlying the genetic architecture of natural variation in gene expression assayed in flushing leaf buds of P. tremula and that connectivity within the co-expression network is linked to the strength of purifying selection.

SUBMITTER: Mahler N

PROVIDER: S-EPMC5407845 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Gene co-expression network connectivity is an important determinant of selective constraint.

Mähler Niklas N Wang Jing J Terebieniec Barbara K BK Ingvarsson Pär K PK Street Nathaniel R NR Hvidsten Torgeir R TR

PLoS genetics 20170413 4

While several studies have investigated general properties of the genetic architecture of natural variation in gene expression, few of these have considered natural, outbreeding populations. In parallel, systems biology has established that a general feature of biological networks is that they are scale-free, rendering them buffered against random mutations. To date, few studies have attempted to examine the relationship between the selective processes acting to maintain natural variation of gen ...[more]

PMID: 28406900

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Project description:BackgroundIn recent years, the relaxin family of signaling molecules has been shown to play diverse roles in mammalian physiology, but little is known about its diversity or physiology in teleosts, an infraclass of the bony fishes comprising approximately 50% of all extant vertebrates. In this paper, 32 relaxin family sequences were obtained by searching genomic and cDNA databases from eight teleost species; phylogenetic, molecular evolutionary, and syntenic data analyses were conducted to understand the relationship and differential patterns of evolution of relaxin family genes in teleosts compared with mammals. Additionally, real-time quantitative PCR was used to confirm and assess the tissues of expression of five relaxin family genes in Danio rerio and in situ hybridization used to assess the site-specific expression of the insulin 3-like gene in D. rerio testis.ResultsUp to six relaxin family genes were identified in each teleost species. Comparative syntenic mapping revealed that fish possess two paralogous copies of human RLN3, which we call rln3a and rln3b, an orthologue of human RLN2, rln, two paralogous copies of human INSL5, insl5a and insl5b, and an orthologue of human INSL3, insl3. Molecular evolutionary analyses indicated that: rln3a, rln3b and rln are under strong evolutionary constraint, that insl3 has been subject to moderate rates of sequence evolution with two amino acids in insl3/INSL3 showing evidence of positively selection, and that insl5b exhibits a higher rate of sequence evolution than its paralogue insl5a suggesting that it may have been neo-functionalized after the teleost whole genome duplication. Quantitative PCR analyses in D. rerio indicated that rln3a and rln3b are expressed in brain, insl3 is highly expressed in gonads, and that there was low expression of both insl5 genes in adult zebrafish. Finally, in situ hybridization of insl3 in D. rerio testes showed highly specific hybridization to interstitial Leydig cells.ConclusionsContrary to previous studies, we find convincing evidence that teleosts contain orthologues of four relaxin family peptides. Overall our analyses suggest that in teleosts: 1) rln3 exhibits a similar evolution and expression pattern to mammalian RLN3, 2) insl3 has been subject to positive selection like its mammalian counterpart and shows similar tissue-specific expression in Leydig cells, 3) insl5 genes are highly represented and have a relatively high rate of sequence evolution in teleost genomes, but they exhibited only low levels of expression in adult zebrafish, 4) rln is evolving under very different selective constraints from mammalian RLN. The results presented here should facilitate the development of hypothesis-driven experimental work on the specific roles of relaxin family genes in teleosts.

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Gene co-expression network connectivity is an important determinant of selective constraint.

Publications

Gene co-expression network connectivity is an important determinant of selective constraint.

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