Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats

Abstract

There are over 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in human evolution and genomic variation, they have yet to be studied collectively and in detail, partially due to their large size, variability, and predominant location in non-coding regions. Here, we examine 467 VNTRs that are human-specific expansions, unique to one location in the genome, and not associated with retrotransposons. We leverage publicly available long-read genomes – including from the Human Genome Structural Variant Consortium – to ascertain the exact nucleotide composition of these VNTRs, and compare their composition of alleles. We then confirm repeat unit composition in over 3000 short-read samples from the 1000 Genomes Project. Our analysis reveals that these VNTRs contain remarkably structured repeat motif organization, modified by frequent deletion and duplication events. While overall VNTR compositions tend to remain similar between 1000 Genomes Project super-populations, we describe a notable exception with substantial differences in repeat composition (in PCBP3), as well as several VNTRs that are significantly different in length between super-populations (in ART1, PROP1, WDR60, and LOC102723906). We also observe that most of these VNTRs are expanded in archaic human genomes, yet remain stable in length between single generations. Collectively, our findings indicate that repeat motif variability, repeat composition, and repeat length are all informative modalities to consider when characterizing VNTRs and their contribution to genomic variation.

Repeat polymorphisms in non-coding DNA underlie top genetic risk loci for glaucoma and colorectal cancer

“…However, we were unable to use adVNTR because it requires sequencing reads to span a VNTR, and the majority of VNTR loci (90%) had an allele longer than the read length in SSC (150bp). While ExpansionHunter is capable of genotyping repeats longer than the read length, it was designed primarily for STR genotyping and assumes that different repeat units are mostly identical in sequence, whereas many VNTRs exhibit repeat motif variability (Course et al 2021). Beyond needing to overcome these specific limitations, we were also motivated to apply methods that leverage haplotype sharing among unrelated individuals in large cohorts to refine genotypes, increasing power to detect downstream associations (Mukamel et al 2021).…”

Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

“…New technologies that enable long contiguous sequence reads (from Pacific Biosciences and Oxford Nanopore Technologies) and optical identification of longrange structural changes (from Bionano Genomics), combined with reference-free assemblies and higher quality annotations for great ape genomes 46,48,80-83 can resolve complex human-specific genomic changes. These new approaches make it possible to systematically identify insertions 46 , deletions 46 , variable number tandem repeats (VNTRs) 84,85 and inversions 86 that arose along the human lineage. Centromeric and telomeric sequences remain particularly difficult to sequence and compare, but recent advances now enable telomere-totelomere sequence comparisons between humans and apes 40,81,87,88 .…”

Detecting tandem repeat variants in coding regions using code-adVNTR

“…First, polymerase slippage may lead to changes in the total motif count; second, point mutations might scar and modify existing motifs. Therefore, many VNTRs are often composed of multiple distinct motifs (Course et al, 2021) (Figure 1A), each only approximately similar to the other. The VNTRs themselves can be denoted as ''short'' if they can be completely encompassed by short reads, and ''long'' otherwise.…”