Adapting Biased Gene Conversion theory to account for intensive GC-content deterioration in the human genome by novel mutations

Paudel, Rajan; Fedorova, Larisa; Fedorov, Alexei

doi:10.1371/journal.pone.0232167

Cited by 3 publications

(4 citation statements)

References 41 publications

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“…This process, called GC-biased gene conversion is quite prevalent in metazoans ( Duret and Galtier, 2009 ). It has been estimated that each generation the average human genome gains roughly 100 de novo single nucleotide mutations ( Chintalapati and Moorjani, 2020 ), and experiences 13 GC-biased gene conversion events ( Paudel et al, 2020 ). When one considers that at most only 10% of all mutations occur in functional parts of the genome ( Lindblad-Toh et al, 2011 ; Ward and Kellis, 2012 ; Rands et al, 2014 ; Graur, 2017 ), GC-biased gene conversion has at least as much influence over genomic content as selection, and this has been observed in the human genome ( Pouyet et al, 2018 ).…”

Section: Mutational Biasmentioning

confidence: 99%

Non-Darwinian Molecular Biology

Palazzo

Kejiou

2022

Front. Genet.

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With the discovery of the double helical structure of DNA, a shift occurred in how biologists investigated questions surrounding cellular processes, such as protein synthesis. Instead of viewing biological activity through the lens of chemical reactions, this new field used biological information to gain a new profound view of how biological systems work. Molecular biologists asked new types of questions that would have been inconceivable to the older generation of researchers, such as how cellular machineries convert inherited biological information into functional molecules like proteins. This new focus on biological information also gave molecular biologists a way to link their findings to concepts developed by genetics and the modern synthesis. However, by the late 1960s this all changed. Elevated rates of mutation, unsustainable genetic loads, and high levels of variation in populations, challenged Darwinian evolution, a central tenant of the modern synthesis, where adaptation was the main driver of evolutionary change. Building on these findings, Motoo Kimura advanced the neutral theory of molecular evolution, which advocates that selection in multicellular eukaryotes is weak and that most genomic changes are neutral and due to random drift. This was further elaborated by Jack King and Thomas Jukes, in their paper “Non-Darwinian Evolution”, where they pointed out that the observed changes seen in proteins and the types of polymorphisms observed in populations only become understandable when we take into account biochemistry and Kimura’s new theory. Fifty years later, most molecular biologists remain unaware of these fundamental advances. Their adaptionist viewpoint fails to explain data collected from new powerful technologies which can detect exceedingly rare biochemical events. For example, high throughput sequencing routinely detects RNA transcripts being produced from almost the entire genome yet are present less than one copy per thousand cells and appear to lack any function. Molecular biologists must now reincorporate ideas from classical biochemistry and absorb modern concepts from molecular evolution, to craft a new lens through which they can evaluate the functionality of transcriptional units, and make sense of our messy, intricate, and complicated genome.

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Section: Mutational Biasmentioning

confidence: 99%

Non-Darwinian Molecular Biology

Palazzo

Kejiou

2022

Front. Genet.

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“…Since the relative frequency of the SNPs in the first bin (0–1%) is more than 20 times larger than the rest of the bins, the first bin was excluded from Figure 1 in order to remove scale distortion. Figure 1 also does not show the last 50 bins (from 51% to 100%) because these frequent alternative alleles are highly enriched by derived alleles instead of ancestral ones, which causes wrong conclusions (e.g., see Paudel and co-authors [ 15 ]). However, the full set of data for all 100 bins are presented in the Supplementary Table S1 .…”

Section: Resultsmentioning

confidence: 99%

“…For example, there is a significant excess of mutations that convert G–C base pairs into A–T base pairs in the human genome than the reverse; mutations that convert A–T base pairs into G–C. However, there is no deterioration of GC-content in humans because the initial excess of G–C to A–T mutations is compensated by the Biased Gene Conversion that operates on the level of DNA reparation of mismatched base pairs in DNA heteroduplexes [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides

Fedorova¹,

Mulyar²,

Lim³

et al. 2022

Genes

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The public UCNEbase database, comprising 4273 human ultra-conserved noncoding elements (UCNEs), was thoroughly investigated with the aim to find any nucleotide signals or motifs that have made these DNA sequences practically unchanged over three hundred million years of evolution. Each UCNE comprises over 200 nucleotides and has at least 95% identity between humans and chickens. A total of 31,046 SNPs were found within the UCNE database. We demonstrated that every human has over 300 mutations within 4273 UCNEs. No association of UCNEs with non-coding RNAs, nor preference of a particular meiotic recombination rate within them were found. No sequence motifs associated with UCNEs nor their flanking regions have been found. However, we demonstrated that UCNEs have strong nucleotide and dinucleotide sequence abnormalities compared to genome averages. Specifically, UCNEs are depleted for CC and GG dinucleotides, while GC dinucleotides are in excess of 28%. Importantly, GC dinucleotides have extraordinarily strong stacking free-energy inside the DNA helix and unique resistance to dissociation. Based on the adjacent nucleotide stacking abnormalities within UCNEs, we conjecture that peculiarities in dinucleotide distribution within UCNEs may create unique 3D conformation and specificity to bind proteins. We also discuss the strange dynamics of multiple SNPs inside UCNEs and reasons why these sequences are extraordinarily conserved.

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“…These authors also hypothesise that the coexistence of elements with drastically different base compositions suggests that these elements may be using different strategies to persist and multiply in the genome of their host. Similarly, other authors proposed that in addition to gBGC, there may be additional, still uncharacterized molecular mechanisms that either preserve genomic regions with biased nucleotide compositions from mutational degradation or fail to degrade such inhomogeneities in specific chromosomal regions [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative Approach to Fish Cytogenetics in the Context of Vertebrate Genome Evolution

Borůvková

Howell

Matoulek

et al. 2021

Genes

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Our novel Python-based tool EVANGELIST allows the visualization of GC and repeats percentages along chromosomes in sequenced genomes and has enabled us to perform quantitative large-scale analyses on the chromosome level in fish and other vertebrates. This is a different approach from the prevailing analyses, i.e., analyses of GC% in the coding sequences that make up not more than 2% in human. We identified GC content (GC%) elevations in microchromosomes in ancient fish lineages similar to avian microchromosomes and a large variability in the relationship between the chromosome size and their GC% across fish lineages. This raises the question as to what extent does the chromosome size drive GC% as posited by the currently accepted explanation based on the recombination rate. We ascribe the differences found across fishes to varying GC% of repetitive sequences. Generally, our results suggest that the GC% of repeats and proportion of repeats are independent of the chromosome size. This leaves an open space for another mechanism driving the GC evolution in vertebrates.

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Adapting Biased Gene Conversion theory to account for intensive GC-content deterioration in the human genome by novel mutations

Abstract: We examined seventy million well-characterized human mutations, and their impact on G +C-compositional dynamics, in order to understand the formation and maintenance of major genomic nucleotide sequence patterns. Among novel mutations, those that change a strong

Cited by 3 publications

References 41 publications

Non-Darwinian Molecular Biology

Non-Darwinian Molecular Biology

Nucleotide Composition of Ultra-Conserved Elements Shows Excess of GpC and Depletion of GG and CC Dinucleotides

Quantitative Approach to Fish Cytogenetics in the Context of Vertebrate Genome Evolution

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