Can GC content at third-codon positions be used as a proxy for isochore composition?

Area of Science:

• Genomics
• Bioinformatics
• Molecular Evolution

Background:

• The isochore theory posits that vertebrate genomes comprise large regions with homogeneous GC content.
• Historically, GC content at third-codon positions (GC3) served as a proxy for isochore GC composition.
• Despite genomic data availability, GC3 is still sometimes misused as a proxy for isochore composition.

Purpose of the Study:

• To evaluate the reliability of GC3 as a proxy for isochore GC content.
• To compare GC3 with GC content in flanking genomic sequences (GCf) across multiple vertebrate species.

Main Methods:

• Analysis of genic and genomic sequences from human, chimpanzee, cow, mouse, rat, chicken, and zebrafish.
• Quantification of GC3 and GCf variation and correlation.
• Comparison of orthologous gene pairs to assess interspecies GC correlations.

Main Results:

• GC3 explains only a minor fraction of GC content variation in flanking genomic sequences (GCf).
• The correlation between GC3 and GCf diminishes rapidly with increasing distance from genes.
• GC3 exhibits higher variation than GCf, rendering their values incomparable.
• Orthologous gene pairs show strong GC3 correlation but weak GCf correlation between closely related species.

Conclusions:

• GC3 is an inadequate stand-in for the isochoric composition of vertebrate genomes.
• Genomic sequence analysis is crucial for accurate assessment of isochore properties.