TY - JOUR
T1 - Genes with a large intronic burden show greater evolutionary conservation on the protein level
AU - Gorlova, Olga
AU - Fedorov, Alexey
AU - Logothetis, Christopher
AU - Amos, Christopher
AU - Gorlov, Ivan
N1 - Funding Information:
This research was supported in part by the David H. Koch Center for Applied Research of Genitourinary Cancers and the NIH grants 5 R01 CA149462 to OYG and 5 P30 CA016672 (MD Anderson’s Cancer Center Support Grant).
PY - 2014/3/16
Y1 - 2014/3/16
N2 - Background: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. Results: We found a positive correlation between the level of evolutionary conservation of a gene and its intronic burden. The level of evolutionary conservation was estimated using the conservation index (CI). The CI value was determined on the basis of the most distant ortholog of the human protein sequence and ranged from 0 (the gene was unique to the human genome) to 9 (an ortholog of the human gene was detected in plants). In multivariable model, both the number of introns and total intron size remained significant predictors of CI. We also found that the number of alternative splice variants was positively correlated with CI.The expression level of a gene was negatively correlated with the number of introns and total size of intronic region. Genes with a greater intronic burden had lower density of missense and nonsense mutations in the coding regions of the gene, which suggests that they are under a stronger pressure from purifying selection. Conclusions: We identified a positive association between intronic burden and CI. One of the possible explanations of this is the idea of a cost-benefits balance. Evolutionarily conserved (functionally important) genes can "afford" the negative consequences of maintaining multiple introns because these consequences are outweighed by the benefit of maintaining the gene. Evolutionarily conserved and functionally important genes may use introns to create novel splice variants to tune the gene function to developmental stage and tissue type.
AB - Background: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. Results: We found a positive correlation between the level of evolutionary conservation of a gene and its intronic burden. The level of evolutionary conservation was estimated using the conservation index (CI). The CI value was determined on the basis of the most distant ortholog of the human protein sequence and ranged from 0 (the gene was unique to the human genome) to 9 (an ortholog of the human gene was detected in plants). In multivariable model, both the number of introns and total intron size remained significant predictors of CI. We also found that the number of alternative splice variants was positively correlated with CI.The expression level of a gene was negatively correlated with the number of introns and total size of intronic region. Genes with a greater intronic burden had lower density of missense and nonsense mutations in the coding regions of the gene, which suggests that they are under a stronger pressure from purifying selection. Conclusions: We identified a positive association between intronic burden and CI. One of the possible explanations of this is the idea of a cost-benefits balance. Evolutionarily conserved (functionally important) genes can "afford" the negative consequences of maintaining multiple introns because these consequences are outweighed by the benefit of maintaining the gene. Evolutionarily conserved and functionally important genes may use introns to create novel splice variants to tune the gene function to developmental stage and tissue type.
KW - Evolutionary conservation
KW - Exon/intron structure
KW - Intronic burden
UR - http://www.scopus.com/inward/record.url?scp=84899110854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899110854&partnerID=8YFLogxK
U2 - 10.1186/1471-2148-14-50
DO - 10.1186/1471-2148-14-50
M3 - Article
C2 - 24629165
AN - SCOPUS:84899110854
SN - 1471-2148
VL - 14
JO - BMC Evolutionary Biology
JF - BMC Evolutionary Biology
IS - 1
M1 - 50
ER -