Increased mutation and gene conversion within human segmental duplications.

Area of Science:

• Genomics
• Human Genetics
• Evolutionary Biology

Background:

• Segmental duplications (SDs) present mapping challenges for short-read sequencing data, limiting the study of single-nucleotide variants (SNVs) within these regions.
• Understanding SNV patterns in SDs is crucial for comprehending genome evolution and disease association.

Purpose of the Study:

• To systematically assess SNVs in human segmental duplications (SDs) by overcoming short-read mapping limitations.
• To investigate the role of interlocus gene conversion (IGC) in SNV patterns within SDs.
• To characterize the mutational spectrum and evolutionary age of SNVs in SDs.

Main Methods:

• Construction of 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes.
• Comparison of SNV patterns between unique and duplicated genomic regions.
• Development of a genome-wide map of IGC donors and acceptors, including analysis of affected protein-coding genes.
• Application of a coalescent framework to assess the evolutionary age of SD regions.

Main Results:

• Human SNVs are elevated by 60% in SDs compared to unique regions.
• At least 23% of this increase is attributed to interlocus gene conversion (IGC), with extensive sequence conversion observed.
• A genome-wide map identified numerous IGC hotspots affecting exons of approximately 800 protein-coding genes, with some genes showing significant relocation.
• SD regions are slightly older evolutionarily than unique sequences, likely due to IGC.
• SNVs in SDs exhibit a distinct mutational spectrum, including increased transversions and reduced CpG-associated mutations, contributing to higher GC content.

Conclusions:

• Interlocus gene conversion significantly contributes to the elevated SNV rate in human segmental duplications.
• The study provides a comprehensive map of IGC activity and its impact on protein-coding genes within SDs.
• Distinct mutational properties of SNVs in SDs likely maintain higher GC content, influenced by GC-biased conversion between paralogous sequences.