Biology subjects

Caceres, M.

Publications and source records attributed to Caceres, M..

9 recordsLinked to original sources

bioRxiv2026

Bias in diversity estimators and neutrality tests induced by neutral polymorphic structural variants

Estimators of genetic diversity and neutrality tests derived from the site frequency spectrum (SFS), such as Wattersons{theta} W, nucleotide diversity{pi} , Tajimas D, and Fay and Wus H, are designed to be interpreted relative to a baseline defined by the standard neutral SFS. In genomic regions strongly linked to a polymorphic structural variant (SV), deviations from these baselines occur even under strict neutrality: conditioning on an SV at known frequency partitions samples into SV and non-SV haplotypes and distorts the SFS for linked neutral mutations. These deviations are well understood for genomic inversions under long-term balancing selection. However, not all SVs are under strong selection, and the evolution of some SVs may be better approximated as neutral. Here we derive analytical expectations for the unfolded (and, when necessary, folded) SFS of single nucleotide polymorphisms conditional on neutral linked polymorphic SVs, including inversions, deletions, insertions, and introgressions. We use these expectations to quantify the resulting bias in standard diversity estimators and neutrality tests as a function of SV frequency and type. Finally, we discuss approaches to build corrected estimators of diversity and neutrality tests that are unbiased/centered after accounting for the presence and frequency of the SV.

genetics↗

bioRxiv2026

Tracing the expansion of p53 retrogenes in elephant species: A foundation for functional insights.

Elephants have evolved multiple TP53 copies through a retrotransposition event followed by successive duplications. Some of these TP53 retrogenes (RTGs) are expressed and hypothesized to have functional roles in cellular regulation. However, comparative genomic studies on TP53 evolution and function are limited due to scarce genomic data for elephants and other afrotherians. Most existing research relies on scaffold assemblies of Loxodonta africana (LoxAfr3 and LoxAfr4), with some focus on Elephas maximus chromosomal assembly. In this in silico study, we analyzed three elephant genomes to validate TP53 RTGs, assess their copy variation, and trace their evolution. For the first time we describe 29 TP53 RTGs in E. maximus versus 18-19 in L. africana. These copies show sequence variation, especially in the duplicated regions and their flanking repetitive elements. Chromosomal mapping in E. maximus revealed that two major classes of TP53 RTGs are consistently arranged in pairs on chromosome 27, which harbours 27 of the 29 identified copies. The observed distribution strongly supports an evolutionary model in which large-scale genomic segments, each encompassing at least two retrogenes of different groups, were duplicated early in the elephant lineage, driving the extensive amplification of TP53 RTGs, as suggested also by the patterns of the flanking repetitive elements. The TP53 RTGs expansion was followed by a unique inversion on chromosome 27 that separates the duplication clusters. Thus, this study enhances our understanding of the elephants multi-p53 system, linked to cancer resistance, body size, and Petos paradox, and supports ongoing research into functional aspects. Significance StatementThis study uncovers the complex genomic architecture of elephant TP53 RTGs, which have diversified into two phylogenetically distinct types present in both African and Asian elephants. While both species share these 2 types, they differ substantially in copy number (18 in African versus 28 in Asian elephants), and in sequence variation, highlighting lineage-specific evolutionary trajectories. Detailed sequence analyses of the chromosomal organization of these copies in the Elephas maximus high-quality genome assembly, particularly the cluster on chromosome 27, indicates that they arose from stepwise duplications of extended genomic segments, which likely facilitated both the expansion and regulatory diversification of the TP53 RTGs repertoire. Comparative analysis with other mammals reveals an elephant-specific inversion that reorganized the expanded TP53 RTGs copies, creating a new genomic configuration that could have influenced the regulation and expression of some of the p53 RTGs. Therefore, this work advances our understanding of how evolutionary pressures shaped the landscape of TP53 RTGs and their flanking genetics elements in elephants. By identifying accurately the retrogene copy numbers, sequences and putative functional domains, it establishes a critical foundation for future studies investigating their functional roles in DNA damage and genome stability.

evolutionary biology↗

bioRxiv2026

Accurate imputation of inversions in human genomes using different algorithms and data sources

Complex genomic regions harbor different structural arrangements that can mutate quite rapidly, which makes determining their functional effects very difficult. Characterization of inversions originated by homologous mechanisms is especially challenging due to the presence of inverted repeats at the breakpoints and the fact that most of them are recurrent. Imputation can infer missing genotypes, but it has been mainly limited to simple variants and little is known about how well it works for human inversions. Here, we tested five common imputation programs to impute a set of 52 inversions experimentally genotyped in multiple samples that lacked SNPs in perfect linkage disequilibrium. Using whole genome sequencing data and simulated microarrays with variable SNP density, we found that 40.4-75.5% of inversions could be accurately imputed in three human populations by at least one program, with results depending mainly on the number of SNPs available, the genotyped samples and the recurrence of inversions. Also, genotype probability filtering was a key factor for inversion imputation accuracy. In particular, Minimac4 and IMPUTE5 showed more accurately imputed inversions and less poorly imputed individuals with respect to the other methods. This work therefore contributes to optimize inversion imputation, making possible the study of their functional impact.

genomics↗

bioRxiv2025

Resolving the full set of human polymorphic inversions and other complex variants from ultra-long read data

Inversions are a unique type of balanced structural variants (SVs) with important consequences in multiple organisms. However, despite considerable effort, this and other complex SVs remain poorly characterized due to the presence of large repeats. New techniques are finally allowing us to identify the full spectrum of human inversions, but the number of individuals analyzed is still quite limited. Here, we take advantage of Oxford Nanopore Technologies (ONT) long reads to characterize an exhaustive catalogue of 612 candidate inversions between 197 bp and 4.4 Mb of length and flanked by <190-kb long inverted repeats (IRs). For that, we developed a bioinformatic package to identify inversion alleles reliably from long read data. Next, using a combination of different DNA extraction, library preparation, and ONT sequencing protocols, we showed that ultra-long reads (50-100 kb) and adaptive sampling are an efficient method to detect most human inversions. Lastly, by analyzing ONT data from 54 diverse individuals, 87-99% of the inversions could be genotyped in each sample, depending mainly on read and IR length and genome coverage. Both orientations were observed for 155 of the analyzed regions (frequency 0.01-0.49), which multiplies by three the polymorphic IR-mediated inversions studied in detail so far. Moreover, we found more than 300 additional independent SVs in the studied regions and resolved several complex rearrangements. Our work therefore provides an accurate benchmark of those inversions that typically escape most analyses, improving existing resources, such as the Pangenome. In addition, it demonstrates the potential of nanopore sequencing to determine the functional impact of missing human genomic variation.

genomics↗

bioRxiv2024

Exploiting uniqueness: seed-chain-extend alignment on elastic founder graphs

Sequence-to-graph alignment is a central challenge of computational pangenomics. To overcome the theoretical hardness of the problem, state-of-the-art tools use seed-and-extend or seed-chain-extend heuristics to alignment, therefore reducing the computational resources required for the task. However, two main problems still remain: on the one hand, the daunting amount of sequencing data requires us to trade alignment accuracy with computational resources; on the other hand, current graph representations of pangenomes introduce an excessive amount of spurious recombinations. In this paper, we implement a complete seed-chain-extend alignment workflow based on indexable elastic founder graphs (iEFGs), a class of graphs built from aligned sequences and supporting fast pattern matching while reducing the number of artificial recombinations. We show how to construct iEFGs from the variations to a linear reference, find high-quality seeds, and extend them using GraphAligner, at the scale of a telomere-to-telomere assembled human chromosome. The main ingredient of our workflow is the use and the efficient computation of semi-repeat-free seeds (srf), a novel class of iEFG-based seeds introduced in this work. The amount of srf seeds is two orders of magnitude less than that of minimizers at the human chromosome level while maintaining comparable speed. Thanks to the uniqueness properties of iEFGs, we show that srf-based seeds suffice to maintain high accuracy while leveraging the speed of our tool. To further stress our point, we also implement chaining of seeds on the elastic degenerate string relaxation of the iEFG and show that only chained seeds suffice to achieve high accuracy alignments. Our sequence-to-graph alignment tool and the scripts to replicate our experiments are available in https://github.com/algbio/SRFAligner.

bioinformatics↗

bioRxiv2022

GraphChainer: Co-linear Chaining for Accurate Alignment of Long Reads to Variation Graphs

Aligning reads to a variation graph is a standard task in pangenomics, with downstream applications such as improving variant calling. While the vg toolkit (Garrison et al., Nature Biotechnology, 2018) is a popular aligner of short reads, GraphAligner (Rautiainen and Marschall, Genome Biology, 2020) is the state-of-the-art aligner of erroneous long reads. GraphAligner works by finding candidate read occurrences based on individually extending the best seeds of the read in the variation graph. However, a more principled approach recognized in the community is to co-linearly chain multiple seeds. We present a new algorithm to co-linearly chain a set of seeds in a string labeled acyclic graph, together with the first efficient implementation of such a co-linear chaining algorithm into a new aligner of erroneous long reads to acyclic variation graphs, GraphChainer. Compared to GraphAligner, GraphChainer aligns 12% to 17% more reads, and 21% to 28% more total read length, on real PacBio reads from human chromosomes 1, 22 and the whole human pangenome. On both simulated and real data, GraphChainer aligns between 95% and 99% of all reads, and of total read length. We also show that minigraph (Li et al., Genome Biology, 2020) and minichain (Chandra and Jain, RECOMB, 2023) obtain an accuracy of less than 60% on this setting. GraphChainer is freely available at https://github.com/algbio/GraphChainer. The datasets and evaluation pipeline can be reached from the previous address.

bioinformatics↗

bioRxiv2021

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression models, we present a catalogue of 35,431,441 variants, including 89,178 SVs ([≥]50bp), 30,325,064 SNVs and 5,017,199 indels, across 785 Illumina high coverage (30X) whole-genomes from the Iberian GCAT Cohort, containing 3.52M SNVs, 606,336 indels and 6,393 SVs in median per individual. The haplotype panel is able to impute up to 14,360,728 SNVs/indels and 23,179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

genomics↗

bioRxiv2019

Determining the impact of uncharacterized inversions in the human genome by droplet digital PCR

Despite the interest in characterizing all genomic variation, the presence of large repeats at the breakpoints of many structural variants hinders their analysis. This is especially problematic in the case of inversions, since they are balanced changes without gain or loss of DNA. Here we tested novel linkage-based droplet digital PCR (ddPCR) assays on 20 inversions ranging from 3.1 to 742 kb and flanked by long inverted repeats (IRs) of up to 134 kb. Among these, we validated 13 inversions predicted by different genome-wide techniques. In addition, we have generated new experimental human population information across 95 African, European and East-Asian individuals for 16 of them, including four already known inversions for which there were no high-throughput methods to determine directly the orientation, like the well-characterized 17q21 inversion. Through comparison with previous data, independent replicates and both inversion breakpoints, we have demonstrated that the technique is highly accurate and reproducible. Most of the studied inversions are frequent and widespread across continents, showing a negative correlation with genetic length. Moreover, all except two show clear signs of being recurrent, and the new data allowed us to define more clearly the factors affecting recurrence levels and estimate the inversion rate across the genome. Finally, thanks to the generated genotypes, we have been able to check inversion functional effects in multiple tissues, validating gene expression differences reported before for two inversions and finding new candidate associations. Our work therefore provides a tool to screen these and other complex genomic variants quickly in a large number of samples for the first time, highlighting the importance of direct genotyping to assess their potential consequences and clinical implications.

genomics↗

bioRxiv2018

Functional and evolutionary impact of polymorphic inversions in the human genome

Inversions are one type of structural variants linked to phenotypic differences and adaptation in multiple organisms. However, there is still very little information about inversions in the human genome due to the difficulty of their detection. Here, thanks to the development of a new high-throughput genotyping method, we have performed a complete study of a representative set of 45 common human polymorphic inversions. Most inversions promoted by homologous recombination occur recurrently both in humans and great apes and, since they are not tagged by SNPs, they are missed by genome-wide association studies. Furthermore, there is an enrichment of inversions showing signatures of positive or balancing selection, diverse functional effects, such as gene disruption and gene-expression changes, or association with phenotypic traits. Therefore, our results indicate that the genome is more dynamic than previously thought and that human inversions have important functional and evolutionary consequences, making possible to determine for the first time their contribution to complex traits.

genomics↗