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Related Concept Videos

Exon Recombination02:32

Exon Recombination

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The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes. 
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Single Nucleotide Polymorphisms-SNPs01:05

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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
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A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
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Genome Copying Errors02:46

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DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their  survival. Therefore, the copying errors are checked and repaired at three levels.
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Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
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Related Experiment Video

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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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A second hotspot for pathogenic exon-skipping variants in CDC45.

Kelly Schoch1, Mischa S G Ruegg2, Bridget J Fellows2

  • 1Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.

European Journal of Human Genetics : EJHG
|March 12, 2024
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Summary

Pathogenic variants in the CDC45 gene cause Meier-Gorlin syndrome with craniosynostosis (MGORS7). Exon skipping, particularly in synonymous variants, is a key mechanism impacting DNA replication and disease presentation.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Human Disease

Background:

  • Biallelic pathogenic variants in CDC45 are linked to Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), characterized by short stature and absent/hypoplastic patellae.
  • These variants typically function through a hypomorphic loss-of-function mechanism, impairing CDC45 activity and DNA replication initiation.

Purpose of the Study:

  • To investigate a second cohort of families with CDC45 variants presenting with craniosynostosis and short stature.
  • To further elucidate the pathogenic mechanisms of CDC45 variants, with a focus on alternative splicing events like exon skipping.

Main Methods:

  • Clinical evaluation of a new cohort of patients with craniosynostosis and short stature.
  • Genetic analysis of CDC45 variants within these families.
  • Functional assessment of identified variants, including analysis of alternative splicing and exon skipping.

Main Results:

  • A second cohort confirmed CDC45 variants cause craniosynostosis, short stature, and distinct facial dysmorphisms (e.g., thin eyebrows).
  • Exon skipping, specifically of exon 15, was identified as a consequence of distinct variants, including a synonymous variant enriched in East Asian ancestry.
  • Other variants affected intramolecular interactions or caused intron retention, further disrupting CDC45 function.

Conclusions:

  • Exon skipping is a significant and relatively common pathogenic mechanism for CDC45 variants.
  • Synonymous variants and other seemingly less impactful variants should be carefully evaluated for their role in alternative splicing, especially exon skipping, in genetic disorders like MGORS7.