Biology subjects

Rakyan, V. K.

Publications and source records attributed to Rakyan, V. K..

4 recordsLinked to original sources

bioRxiv2026

Biobank-scale genotyping of Robertsonian translocations reveals hidden structural variation on the human acrocentric chromosomes

Balanced Robertsonian translocation (ROB) is the most common chromosomal rearrangement in humans, with an estimated occurrence of 1 in 800 in newborn studies. Carriers are at increased risk of cancer and often diagnosed at fertility clinics after facing recurrent miscarriages, infertility, or aneuploid offspring. Genotyping carriers with DNA sequencing has been challenging because of gaps and misrepresentation of the translocation fusion site in the human reference genome. Only recently, telomere-to-telomere (T2T) human genomes successfully revealed sequences of the acrocentric short arms, including the most common ROB fusion site. A ROB results in loss of two ribosomal DNA (rDNA) arrays and its adjacent distal sequences, including the highly conserved distal junction (DJ). Here, we present a novel method to type ROB carriers directly from short sequencing reads by estimating DJ copy number. We demonstrate that our method successfully genotypes ROBs using a reference-free approach or alignments to either T2T-CHM13v2 or GRCh38. Applying the method to a cohort of healthy newborns and family members (n=4,172) as well as the UK Biobank (n=490,416), we find candidate ROBs at a frequency consistent with the previously reported 1 in 800 incidence (0.11-0.12%). In addition to ROB carriers, we report the frequency of one DJ loss (9, 2.8-3.4%) or gain (11+, 8.4-9.3%) from the two cohorts and the 1000 Genomes Project (n=3,202), and characterize the underlying structural variation in near-T2T genome assemblies from the Human Pangenome Reference Consortium. Importantly, our method provides the first sequencing-based diagnostic for Robertsonian chromosomes and can be applied to low-coverage sequencing data, enhancing its clinical applicability and enabling new studies of structural variation on the acrocentric chromosomes.

genomics↗

bioRxiv2025

Germline sequence variation within the ribosomal DNA is associated with human complex traits

The ribosome is one of the core macromolecules in the cell. The ribosomal RNAs (rRNA), which are essential components of the ribosome, are coded by the multi-copy ribosomal DNA (rDNA). Despite its highly conserved function, the rDNA displays substantial variation within all species analysed to date. This variation comprises both inter-individual differences in total copy number (CN) as well as inter- and intragenomic sequence variation in the form of single nucleotide variants (SNV) and insertions/deletions (INDELs) across rDNA copies. Whether germline variation of rDNA sequence associates with phenotypic traits in humans is, to date, unknown. Here, using the UK Biobank whole genome sequencing data, we first derive a high confidence list of rDNA-associated SNVs and INDELs that we validate in multiple ways. Using this list, we show that specific rDNA variants associate with several human traits. In particular, traits associated with body size appear enriched in variants within the Expansion Segment 15L region in the 28S rRNA. The strength of these associations does not diminish when accounting for the total rDNA CN of each individual. Our work represents the first large-scale association analysis of human traits with germline sequence variation in the rDNA, a source of human complex trait-relevant genetic variation that has thus far been largely ignored.

genetics↗

bioRxiv2023

Ribosomal DNA copy number is associated with body mass in humans and other mammals

Body mass results from a complex interplay between genetics and environment. The contribution of genetic variation to body mass has been extensively studied, but due to the technical limitations of platforms used for population scale studies, repetitive parts of the genome have not previously been considered. Here we applied genome-wide approaches to identify an association between adult body mass and the copy number (CN) of 45S-ribosomal DNA (rDNA). rDNA codes for the rRNA components of the ribosome and exists in hundreds of copies/cell in mammals. Inter-individual variation in rDNA CN has not previously been documented but has not been associated with a mammalian phenotype. Here, we show that germ-line inherited rDNA CN is associated with post-pubertal growth rate in rats and BMI in adult humans. rDNA CN variation is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This is supported by our observation that it is growth rate and body mass, rather than obesity that are associated with copy number and that these phenotypes emerge prior to adulthood. We present hypotheses for future investigation into the mechanistic basis of this association.

genomics↗

bioRxiv2017

Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

genomics↗