Selective Constraints in Primate Regulatory DNA
Author Information
Author(s): Gaffney Daniel J., Blekhman Ran, Majewski Jacek
Primary Institution: McGill University
Hypothesis
What fraction of regulatory mutations in primates are strongly deleterious?
Conclusion
The study finds that approximately 37% of new spontaneous mutations in primate transcription factor binding sites (TFBSs) are strongly deleterious.
Supporting Evidence
- Approximately 37% of mutations at TFBSs are strongly deleterious.
- Constraint is significantly reduced in human and chimpanzee pCRMs and ChIP-chip sequences compared to macaques.
- The fraction of regulatory mutations driven to fixation by positive selection in humans is not significantly different from zero.
- The level of selective constraint in TFBSs is negatively correlated with the expression breadth of the regulated gene.
- The rate of protein evolution in a transcription factor is positively correlated with the breadth of expression of the gene it regulates.
Takeaway
This study looks at how changes in DNA that control gene expression can affect evolution, finding that many of these changes can be harmful.
Methodology
The study used two datasets of human TFBSs supported by experimental data to estimate levels of selective constraint in regulatory noncoding DNA.
Potential Biases
There may be ascertainment bias in the TRANSFAC annotations, which could affect the results.
Limitations
The study's estimates of selective constraint may be biased upwards due to the use of human genome alignments and potential ascertainment bias in the TFBS dataset.
Participant Demographics
The study focuses on primate species, specifically humans, chimpanzees, and macaques.
Statistical Information
P-Value
p<10−16
Confidence Interval
95% confidence intervals estimated by bootstrapping the data.
Statistical Significance
p<0.05
Digital Object Identifier (DOI)
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