The role of GC-biased gene conversion in shaping the fastest evolving regions of the human genome
Open accessAbstract
GC-biased gene conversion (gBGC) is a recombination-associated evolutionary process that accelerates the fixation of guanine or cytosine alleles, regardless of their effects on fitness. gBGC can increase the overall rate of substitutions, a hallmark of positive selection. Many fast-evolving genes and noncoding sequences in the human genome have GC-biased substitution patterns, suggesting that gBGC-in contrast to adaptive processes-may have driven the human changes in these sequences. To investigate this hypothesis, we developed a substitution model for DNA sequence evolution that quantifies the nonlinear interacting effects of selection and gBGC on substitution rates and patterns. Based on this model, we used a series of lineage-specific likelihood ratio tests to evaluate sequence alignments for evidence of changes in mode of selection, action of gBGC, or both. With a false positive rate of less than 5% for individual tests, we found that the majority (76%) of previously identified human accelerated regions are best explained without gBGC, whereas a substantial minority (19%) are best explained by the action of gBGC alone. Further, more than half (55%) have substitution rates that significantly exceed local estimates of the neutral rate, suggesting that these regions may have been shaped by positive selection rather than by relaxation of constraint. By distinguishing the effects of gBGC, relaxation of constraint, and positive selection we provide an integrated analysis of the evolutionary forces that shaped the fastest evolving regions of the human genome, which facilitates the design of targeted functional studies of adaptation in humans.
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Kostka et al. found that most HARs (76%), including HAR202, underwent an acceleration process better explained by either positive selection or relaxation of constraint rather than by gBGC.
“By using this method, they found that most HARs (76%), including HAR202, underwent an acceleration process better explained by either positive selection or relaxation of constraint (Kostka et al. 2012), rather than by gBGC”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Kostka et al. 2012
The Results section, “gBGC Accounts for the Substitutions in Only a Minority of HARs,” says that 76% of HARs are best explained by a change in selection coefficient without gBGC, and divides them into positive-selection and relaxation-of-constraint classes. The passages do not identify HAR202 as belonging to either class, so the specific claim about HAR202 is not supported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredgBGC was a mechanism found in only 19% of HARs.
“the latter being a mechanism only found in 19% of HARs (Kostka et al. 2012).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Kostka et al. 2012
GC-biased gene conversion (gBGC) is one of the factors that can increase local substitution rates across the genome and is often a confounding factor for the detection of adaptive evolution.
“GC-biased gene conversion (gBGC) is one of the factors that can increase local substitution rates across the genome and is often a confounding factor for the detection of adaptive evolution (Duret and Galtier 2009; Kostka et al. 2012; Capra et al. 2013).”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Kostka et al. 2012
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“By using this method, they found that most HARs (76%), including HAR202, underwent an acceleration process better explained by either positive selection or relaxation of constraint (Kostka et al. 2012), rather than by gBGC, the latter being a mechanism only found in 19% of HARs (Kostka et al. 2012).”
BackgroundMethod
- Authors
- Kostka, D., Hubisz, M. J., Siepel, A., & Pollard, K. S.
- Affiliations
- University of California, San Francisco (US)
- Cornell University (US)
- Corresponding author
- Kostka, D.
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-11-10
- Volume
- 29
- Issue
- 3
- Pages
- 1047-1057
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- PMC
- PMC3278478
- OpenAlex
- W2102029197
- Cited by
- 102
- References
- 43
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 6 · 2023: 13 · 2022: 10 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 9 · 2014: 6 · 2013: 10 · 2012: 2
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM082901, #GM82901)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- GC-biased gene conversion, human accelerated regions, positive selection, substitution rate, substitution patterns, recombination, substitution models, human genome evolution, non-coding sequences
- MeSH terms
- Base Composition, Base Sequence, Gene Conversion, Humans, Models, Genetic, Selection, Genetic, Genome, Human, Likelihood Functions, Sequence Alignment, Evolution, Molecular
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