Non-B DNA and Genome Evolution

Project: Research project

Project Details

Description

PROJECT SUMMARY Despite the availability of efficient technologies and rapidly accumulating data, the function and mutation characteristics of many regions of the genome remain enigmatic. One way to solve this puzzle is through the lens of evolution. The Makova Laboratory uses a combination of experimental and computational techniques to study human genome evolution. The overarching goals are to decipher the mechanistic and evolutionary processes generating genome variation and shaping genome architecture and to uncover the function of, and selection acting on, different parts of the genome. During the next five years, the laboratory’s focus will be on decoding the role of non-canonical (non-B) DNA structures in genome evolution. At certain sequence motifs, DNA is capable of assuming conformations that are different from the classical right-handed double-helix with 10 base pairs per turn (i.e. B DNA). Such motifs constitute as much as 13% of the human genome. Non-B DNA structures include G-quadruplexes, cruciforms, DNA triplexes, and Z-DNA. Their formation is transient. It is sensitive to signals during cell differentiation and development and can b triggered by certain conditions in the cell, including oxidative and replication stress. Non-B DNA motifs are present across the tree of life, and abundant experimental evidence indicates non-B DNA structure formation in mammalian cells. Non-B DNA structures can be viewed as a double-edged sword. On the one hand, their transient formation regulates a multitude of fundamental molecular processes, including the initiation of transcription and of replication. On the other hand, such structures may impede replication, causing increased mutagenesis and chromosomal rearrangements. At present, it is not well understood how non-B structures evolve and influence genome evolution. Of particular interest are the following questions. Do non-B DNA structures affect the progression of replication forks in living cells? Do non-B DNA structures elevate rates of mutations in germline cells and thus serve as mutation hotspots in evolution? Where in the genome do non-B DNA structures evolve under purifying selection and thus are functional? How do evolutionary changes in non-B DNA structures affect their functions? To address these and other questions, we will use specialized experimental and computational approaches and will exploit the complete, telomere-to-telomere, human and ape genome assemblies. These assemblies and approaches will provide a unique opportunity to study non-B DNA structures, which can serve as versatile switches and fine-tunable regulators of variation in molecular processes at different evolutionary time scales—among individual humans, among ape species, and beyond. Addressing the questions of the proposal will illuminate the mechanisms generating human genetic variation, will assist in accurate construction of models in population genetics and molecular evolution, will bring us closer to complete functional annotation of the genome, and, in the future, will inform personalized medicine.
StatusActive
Effective start/end date1/1/2412/31/24

Funding

  • National Institute of General Medical Sciences: $871,160.00

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