Human Variation in Short Regions Predisposed to Deep Evolutionary Conservation
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate. Biology and Biotechnology Division
- National Library of Medicine (NLM), Bethesda, MD (United States). National Center for Biotechnology Information. Computational Biology Branch
The landscape of the human genome consists of millions of short islands of conservation that are 100% conserved across multiple vertebrate genomes (termed ‘‘bricks’’), the majority of which are located in noncoding regions. Several hundred thousand bricks are deeply conserved reaching the genomes of amphibians and fish. Deep phylogenetic conservation of noncoding DNA has been reported to be strongly associated with the presence of gene regulatory elements, introducing bricks as a proxy to the functional noncoding landscape of the human genome. Here, we report a significant overrepresentation of bricks in the promoters of transcription factors and developmental genes, where the high level of phylogenetic conservation correlates with an increase in brick overrepresentation. We also found that the presence of a brick dictates a predisposition to evolutionary constraint, with only 0.7% of the amniota brick central nucleotides being diverged within the primate lineage—an 11-fold reduction in the divergence rate compared with random expectation. Human single-nucleotide polymorphism (SNP) data explains only 3% of primate-specific variation in amniota bricks, thus arguing for a widespread fixation of brick mutations within the primate lineage and prior to human radiation. This variation, in turn, might have been utilized as a driving force for primate- and hominoid-specific adaptation. We also discovered a pronounced deviation from the evolutionary predisposition in the human lineage, with over 20-fold increase in the substitution rate at brick SNP sites over expected values. In addition, contrary to typical brick mutations, brick variation commonly encountered in the human population displays limited, if any, signatures of negative selection as measured by the minor allele frequency and population differentiation (F-statistical measure) measures. These observations argue for the plasticity of gene regulatory mechanisms in vertebrates—with evidence of strong purifying selection acting on the gene regulatory landscape of the human genome, where widespread advantageous mutations in putative regulatory elements are likely utilized in functional diversification and adaptation of species.
- Research Organization:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- Grant/Contract Number:
- AC52-07NA27344
- OSTI ID:
- 1625394
- Journal Information:
- Molecular Biology and Evolution, Vol. 27, Issue 6; ISSN 0737-4038
- Publisher:
- Oxford University PressCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Regulatory and coding genome regions are enriched for trait associated variants in dairy and beef cattle
|
journal | January 2014 |
Natural variability of minimotifs in 1092 people indicates that minimotifs are targets of evolution
|
journal | June 2015 |
The genomic signature of trait-associated variants
|
journal | February 2013 |
Purifying Selection in Deeply Conserved Human Enhancers Is More Consistent than in Coding Sequences
|
journal | July 2014 |
Similar Records
Evolutionary conservation of regulatory elements in vertebrate HOX gene clusters
Evolutionary expansion and divergence in a large family of primate-specific zinc finger transcription factor genes