Developmental biology - Periodicity of Genome|
Gene Mutations Recur At Regular Intervals
DNA damage and repair may occur at regular intervals in our genome...
Researchers at The Institute For Research in Barcelona (IRB), Spain, explain how the origin of genome periodicity [regularity] occurs in eurakyote animals. Eurakyotes are single and multi celled beings that have membranes surrounding organs and organelles which carry out specialized functions. Humans, animals, plants, fungi, and insects have organs or organelles. However, bacteria or prokaryotes are much simpler and do not have membranes separating specific functions they may conduct.
Scientists at the IRB found eukaryotes, from yeast to humans, have periodicity of function ocurring at regular intervals separated by regular genomic sequences. Their results are published in the journal Cell and offer an alternative explanation to the concept of 'natural selection', currently the only accepted explanation to date for why 'sucessful' eucaryote behaviors become sustained over time.
This research demonstrates that DNA damage and repair processes are affected by the consistent generation of sequence periodicity (regularity) within the eukaryotic genome. These processes are influenced by the orientation of A, T, C and G bases on the DNA molecule packaged inside the cell nucleus. The genome appears to favor a balanced distance between these base pairings.
"The answer we provide better explains why our genome and that of other animal species have developed into what they are today."
Núria López-Bigas PhD, Director of the study, Leader of the Biomedical Genomics Lab, IRB, Barcelona,Spain.
The "mysterious" periodicity of the genome
Since the beginning of the 21st century when the DNA sequences of human, mouse and fruit fly genomes were identified, researchers have noticed a consistent regularity in the pairing of A and T bases - adenine (A) and thymine (T). The proportion of A/T pairs increases after every 10 base pair occurs. This periodicity or regularity in A/T base pairs has been associated with how DNA winds around histones. Previously, scientists explained the regularity of A/T base pairings on 'natural selection' which favors their flexibility allowing the DNA molecule to bend around histones and form nucleosomes.
By counting the appearance of mutations distributed in more than 3,000 human tumors, the IRB team established mutations accumulate after every 10 DNA base pairs of A/T appear. Researchers then turned their attention to mutations passed from one generation to another in both humans and plants, to find hereditary mutations also accumulate every 10 base pairs. With this new observation, they deduced periodicity might also explain the A/T sequences in all eukaryotic genomes.
Mutations over millions of years of evolution
IRB scientists now hypothesise that as most mutations are in cytosines (C), that convert into thymines (T), those regions are more prone to mutation. Over millions of years of our existence - these mutations accumulated and have become A/T base pairs.
To test this hypothesis, researchers performed a mathematical simulation of genome evolution and confirmed that periodicity found in eukaryote genomes can arise from mutations that steadily amass into tumors simply as a result of periodicity of A/T mutations.
• Somatic and germline mutation rates show a 10-bp periodicity in nucleosome-occupied DNA
• This periodicity tracks DNA minor groove facing toward and away from the histones
• The orientation of the periodicity depends on the mutational processes active in the tissue
• This has contributed to the AT/CG 10-bp periodicity in eukaryotic genomes
Mutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosome-bound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.
Oriol Pich, Ferran Muiños, Radhakrishnan Sabarinathan, Iker Reyes-Salazar, Abel Gonzalez-Perez, Nuria Lopez-Bigas.
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The DNA molecule. A double helix, winds around histone molecules twice, forming nucleosomes
. The pink regions indicate those enriched in adenine/thymine base pairs. Credit: Iris Joval Granollers.