Biology subjects

Verbiest, M. A.

Publications and source records attributed to Verbiest, M. A..

3 recordsLinked to original sources

bioRxiv2024

Genotyping Short Tandem Repeats Across Copy Number Alterations, Aneuploidies, and Polyploid Organisms

Short tandem repeats (STRs) are a rich source of genetic variation, but are difficult to genotype. While specialized repeat variant callers exist, they typically assume a euploid human genome. This means recent findings regarding phenotypic effects of STR variants in human health and disease cannot be readily extended to polyploid organisms or cancer, which is characterised by copy number alterations (CNAs). Here we present ConSTRain, a novel STR variant caller that explicitly accounts for the copy number of loci in its genotyping approach. We benchmark ConSTRain using a euploid human 100X whole genome sequencing sample where it calls STR allele lengths for over 1.7 x 106 loci in under 20 minutes with an accuracy of 98.28%. Subsequently, we show that ConSTRain resolves complex STR genotypes in an artificial trisomy 21 sample and a polyploid Dwarf Cavendish banana harbouring a large duplication. Finally, we analyse a microsatellite instable colorectal cancer tumoroid, where ConSTRain tackles CNAs and whole-genome duplications. ConSTRain is the first STR variant caller that allows for the investigation of repeats affected by CNAs, aneuploidies, and polyploid genomes. This unlocks the investigation of STRs across a wide range of contexts and organisms where they previously could not be easily studied.

bioinformatics↗

bioRxiv2023

Short tandem repeat mutations regulate gene expression in colorectal cancer

Short tandem repeat (STR) mutations are prevalent in colorectal cancer (CRC), especially in tumours with the microsatellite instability (MSI) phenotype. While STR length variations are known to regulate gene expression under physiological conditions, the functional impact of STR mutations in CRC remains unclear. Here, we integrate STR mutation data with clinical information and gene expression levels to study the gene regulatory effects of STR mutations in CRC. We confirm that STR mutability in CRC highly depends on the MSI status, repeat unit size, and repeat length. Furthermore, we present a set of 1244 putative expression STRs (eSTRs) for which the STR length is associated with gene expression levels in CRC tumours. The length of 73 eSTRs is associated with expression levels of cancer-related genes, nine of which are CRC-specific genes. We show that linear models describing eSTR-gene expression relationships allow for predictions of gene expression changes in response to eSTR mutations. Moreover, we found an increased mutability of eSTRs in MSI tumours. Our evidence of gene regulatory roles for eSTRs in CRC highlights a mostly overlooked way through which tumours may modulate their phenotypes. The increased mutability of eSTRs in MSI tumours may be an early indication that eSTR mutations can confer a selective advantage to tumours. Future extensions of our findings into larger cohorts could uncover new STR-based targets in the treatment of cancer.

cancer biology↗

bioRxiv2022

Characterization of a Novel Hyper-Variable Variable Number Tandem Repeat in the Dopamine Transporter Gene (SLC6A3)

The dopamine transporter gene, SLC6A3, has received substantial attention in genetic association studies of various phenotypes. Although some variable number tandem repeats (VNTRs) present in SLC6A3 have been tested in genetic association studies, results have not been consistent. VNTRs in SLC6A3 that have not been examined genetically were characterized. Tandem Repeat Annotation Library (TRAL) was used to characterize the VNTRs of 64 unrelated long-read haplotype-phased SLC6A3 sequences. Sequence similarity of each repeat unit of the five VNTRs is reported, along with the correlations of SNP-SNP, SNP-VNTR and VNTR-VNTR alleles across the gene. One of these VNTRs is a novel hyper-VNTR (hyVNTR) in intron 8 of SLC6A3, which contains a range of 3.4-133.4 repeat copies and has a consensus sequence length of 38bp, with 82% G+C content. The 38-base repeat was predicted to form G-quadruplexes in silico and was confirmed by circular dichroism spectroscopy. Additionally, this hyVNTR contains multiple putative binding sites for PRDM9, which, in combination with low levels of linkage disequilibrium around the hyVNTR, suggests it might be a recombination hotspot. Summary BlurbThis VNTR has a heterozygosity value of 0.93, forms G-tetrads, and is in low linkage disequilibrium with surrounding sequence, making it a new site for genetic analysis.

genomics↗