Copy number variation arising from gene conversion on the human Y chromosome

Area of Science:

• Human Genetics
• Molecular Biology
• Genomics

Background:

• Copy number variation (CNV) is a significant source of genetic diversity in humans.
• The human Y chromosome harbors unique genomic structures, including inverted repeats and noncoding RNA genes.
• Understanding CNV mechanisms is crucial for deciphering genetic variation and its impact.

Purpose of the Study:

• To characterize copy number variation in a specific 10 kb region overlapping the TTTY22 long intergenic noncoding RNA (lincRNA) gene on the human Y chromosome.
• To investigate the mutational mechanisms responsible for generating these copy number changes.
• To determine the frequency and evolutionary implications of this CNV in the general population.

Main Methods:

• Analysis of copy number variation in 1234 individuals from the 1000 Genomes Project.
• Validation using breakpoint PCR, fiber-FISH, and 10× Genomics Chromium linked-read sequencing.
• Phylogenetic mapping of CNV events and investigation of flanking paralogous sequence variants.

Main Results:

• Individuals exhibit 0-3 copies of the TTTY22 gene region, with 0 copies found in 266 individuals and 1 copy in 943.
• At least 20 mutational events were identified, with gene conversion being the predominant mechanism for 0-2 copy events.
• These gene conversion events are among the longest non-allelic gene conversions reported, exceeding 30 kb in some instances.
• Three copies arose from a single, large 420 kb duplication event.

Conclusions:

• Gene conversion is an under-appreciated mechanism driving copy number changes in the human genome.
• This study reveals the substantial size of gene conversion events that can occur.
• The findings contribute to understanding the structural variation and evolutionary dynamics of the human Y chromosome.