Biology subjects

Avvaru, A. K.

Publications and source records attributed to Avvaru, A. K..

6 recordsLinked to original sources

bioRxiv2026

A family portrait of the genomic factors shaping tandem repeat mutagenesis

Tandem repeats (TRs) are among the most mutable loci in the human genome, but the genomic determinants of TR mutagenesis remain mysterious. We used PacBio HiFi long-read sequencing to profile nearly eight million TR loci in 28 members of a large, four-generation CEPH/Utah family designated K1463. We identified 1,270 de novo TR expansions and contractions across 20 children in the pedigree. De novo mutations (DNMs) were more likely to occur at loci that were longer, composed of uninterrupted motif sequences, and heterozygous in the parental germline. Children born to older fathers also exhibited more de novo mutations at short tandem repeats (STRs). A total of 43 TR loci were hyper-mutable in K1463, expanding or contracting up to twelve times across the pedigree. Among hyper-mutable loci that comprised multiple motifs (i.e., "complex" loci), specific motifs expanded and contracted more often than others; for example, all ten DNMs at a complex, hyper-mutable locus near the non-coding RNA LINC03021 involved the same 19bp motif. The mutability of particular motifs may be attributable to allele length, as 95% of DNMs at complex loci were expansions and contractions of the most abundant motif on a parental haplotype. However, future work will be required to disentangle the effects of nucleotide content and allele length on motif-specific mutability, especially at hyper-mutable TRs. Overall, this study combines long-read sequencing technologies with new software tools to comprehensively investigate the factors that influence TR mutagenesis.

genomics↗

bioRxiv2025

Long-read sequencing reveals extensive FMR1 somatic mosaicism in Fragile-X associated tremor/ataxia syndrome in human brain

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a CGG repeat expansion in the 5 untranslated region of the X-linked Fragile X messenger ribonucleoprotein 1 (FMR1). Although the CGG repeat tract is known for instability that has been posited to contribute to clinical heterogeneity, the extent of somatic variation in human brain remains unclear, in part due to the technical limitations of sequencing long tandem repeats. Here, we quantified FMR1 somatic variation in post-mortem brain tissue from individuals with FXTAS (n = 6) and Fragile X syndrome (FXS, n = 2) by applying amplification-free, targeted, long-read sequencing. This approach uncovered remarkable somatic mosaicism in repeat size and methylation in FXTAS, including somatic expansions and contractions which were not resolvable with traditional approaches. For example, in FXTAS, we identified somatic expansions to over 6000 base pairs in length as well as contractions to below the pathogenic range. We also identified unexpected patterns of methylation mosaicism on pre and full mutations. On the other hand, we replicated prior findings suggesting differential CGG expansion on the active X-chromosome in XX females. Finally, we examined the above cohort for expansions in 19 additional disease-associated repeat loci. Remarkably, we identified additional expansions in 5 out of 8 affected individuals, in FXN and RFC1. This work provides new insight into the extensive molecular variation underlying FXTAS in human brain and establishes a framework for studying repeat expansion disorders more broadly, highlighting the potential of long-read sequencing to advance our fundamental understanding of somatic mosaicism of these intractable regions of our genome.

genetics↗

bioRxiv2025

ATaRVa: Analysis of Tandem Repeat Variation from Long Read Sequencing data

Tandem Repeats (TRs) are contiguous repetitions of DNA motifs whose variations modulate key cellular processes and traits. Their expansions are causally linked to over 70 neurological disorders in humans. Historically, genotyping TRs has been challenging due to their low sequence complexity and allele lengths exceeding typical short-read sequencing capabilities. While long-read sequencing improves TR genotyping by spanning large expansions and sequencing native DNA molecules, existing long-read genotypers often are inaccurate, computationally inefficient, and show platform-specific biases. Here, we present ATaRVa, a genotyper that achieves superior accuracy across both PacBio and Oxford Nanopore platforms, while running [~]15x faster than existing tools. Beyond genotyping, ATaRVa features sequence-level motif decomposition and methylation profiling. Evaluated across diverse datasets and genome-wide catalogs, ATaRVa especially excels in low coverage datasets, and accurately identifies known pathogenic expansions in clinical samples. Importantly, by quantifying uninterrupted target motifs in a population scale analysis, the tool systematically resolves false positives caused by benign, interrupted alleles. In addition, we present VisuaMiTRa, an auxiliary interface that enables interactive visualization of motif-level decomposition and base-level methylation of the TR alleles. By combining high computational efficiency with sequence-level structural awareness, ATaRVa provides a highly scalable framework for TR analysis in both population cohorts and clinical settings.

genomics↗

bioRxiv2025

Ribbit: Accurate identification and annotation of complex tandem repeat sequences in genomes

DNA tandem repeats (TRs) are crucial for genomic functions like protein binding, chromatin modulation, splicing, and gene regulation. Abnormal length variations in TRs, especially expansions, are associated with over 60 neurodegenerative diseases. The function and stability of a TR locus is dependent on its sequencing composition and purity. Recent studies report the disease-causing propensity of non-canonical motif expansions in TR loci, and highlight the intricate polymorphism dynamics in complex loci encompassing adjacent, overlapping, and nested TRs. These reports emphasize the need for precise definition and motif decomposition of TR loci. To address this, we present Ribbit, a tool that accurately and efficiently identifies and annotates TR loci in a genome. Ribbit uses 2-bit representation of DNA sequences for rapid identification of TRs of 2-100 bp motif size and resolves complex TR structures. Ribbit efficiently handles imperfections such as indels and substitutions, providing insights into nested and compound TR relationships through detailed motif decomposition. Comparative analyses using simulated data show Ribbit outperforms existing tools like Dot2dot and TRF in terms of runtime and accuracy. Ribbit reports TR loci in the human genome with lower redundancy than TRF and provides resolved TR regions comparable to variation clusters reported in recent catalogues. Therefore, Ribbit can be leveraged to understand the evolution and biology of complex TR regions in large genomes.

bioinformatics↗

bioRxiv2021

DiviSSR: Simple arithmetic for efficient identification of tandem repeats

Numerical or vector representations of DNA sequences have been applied for identification of specific sequence characteristics and patterns which are not evident in their character (A, C, G, T) representations. These transformations often reveal a mathematical structure to the sequences which can be captured efficiently using established mathematical methods. One such transformation, the 2-bit format, represents each nucleotide using only two bits instead of eight for efficient storage of genomic data. Here we describe a mathematical property that exists in the 2-bit representation of tandemly repeated DNA sequences. Our tool, DiviSSR (pronounced divisor), leverages this property and subsequent arithmetic to achieve ultrafast and accurate identification of tandem repeats. DiviSSR can process the entire human genome in [~]30s, and short sequence reads at a rate of >1 million reads/s on a single CPU thread. Our work also highlights the implications of using simple mathematical properties of DNA sequences for faster algorithms in genomics. AvailabilityDiviSSR can be installed directly using python pip. The source code and documentation of DiviSSR are available at https://github.com/avvaruakshay/divissr.git.

bioinformatics↗

bioRxiv2018

Patterns of microsatellite distribution reflect the evolution of biological complexity

Microsatellites, also known as Simple Sequence Repeats (SSRs), are evolutionarily conserved repeat elements distributed non-randomly in all genomes. Many studies have investigated their pattern of occurrence in order to understand their role, but their identification has largely been non-exhaustive and limited to a few related species or model organisms. Here, we identify ~685 million microsatellites from 719 eukaryotes and analyze their evolutionary trends from protists to mammals. We document novel patterns uniquely demarcating closely related species, including in pathogens like Leishmania as well as in higher organisms such as Drosophila, birds, primates, and cereal crops. The distribution of SSRs in coding and non-coding regions reveals taxon-specific variations in their exonic, intronic and intergenic densities. We also show that specific SSRs accumulate at longer lengths in higher organisms indicating an evolutionary selection pressure. In general, we observe greater constraints in the SSR composition of multicellular organisms with complex cell types, while simpler organisms show more diversity. The conserved microsatellite trends and species-specific signatures identified in this study closely mirror phylogenetic relationships and we hypothesize that SSRs are integral components in speciation and the evolution of organismal complexity. The microsatellite dataset generated in this work provides a large number of candidates for functional analysis and unparalleled scope for understanding their roles across the evolutionary landscape.

genomics↗