A novel hypervariable variable number tandem repeat in the dopamine transporter gene (SLC6A3).

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• The dopamine transporter gene (SLC6A3) is crucial for neurotransmission and has been studied in various genetic association studies.
• Previous genetic association studies of SLC6A3 have yielded inconsistent results, particularly concerning variable number tandem repeats (VNTRs).

Purpose of the Study:

• To characterize previously unexamined VNTRs within the SLC6A3 gene.
• To investigate the sequence properties and potential functional significance of these VNTRs, including novel variants.

Main Methods:

• Utilized the Tandem Repeat Annotation Library to analyze 64 long-read haplotype-phased SLC6A3 sequences.
• Characterized sequence similarity, allele correlations (SNP-SNP, SNP-VNTR, VNTR-VNTR), and identified a novel hyper-VNTR (hyVNTR).
• Performed in silico prediction and circular dichroism spectroscopy to assess G-quadruplex formation and identified PRDM9 binding sites.

Main Results:

• Identified five VNTRs in SLC6A3, reporting sequence similarity and allele correlations.
• Discovered a novel hyVNTR in intron 8 with a variable repeat copy number (3.4-133.4) and high G+C content (82%).
• Confirmed the hyVNTR's potential to form G-quadruplexes and identified multiple PRDM9 binding sites, suggesting it as a potential recombination hotspot.

Conclusions:

• The characterization of novel VNTRs in SLC6A3 provides new genetic markers for association studies.
• The identified hyVNTR in intron 8 exhibits unique structural and functional properties, including G-quadruplex formation and PRDM9 binding.
• The hyVNTR's characteristics suggest a potential role as a recombination hotspot, influencing SLC6A3 genetic diversity and association study outcomes.