The next frontier for genomic prediction is computational

G3 Genes Genomes Genetics · 2026-02-01

From the seminal paper by Meeuwissen et al. 2001 to the GSA Journals Series launch in 2015, the field of Genomic Prediction continues to gain momentum. The field is increasingly dynamic, with new technology increasing the scale and scope of the data available. Significant challenges exist in building computational models. Questions of how to appropriately account for different types of data, and which data improve predictions are interwoven. What is the best path forward? What methods will improve predictions? Authors can submit their rejoinder or start a new discussion on one of the many important topics in the field by submitting a Dialogue and Debate article for peer review at G3.

Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes

Cell Reports · 2026-03-23

This study explores the inflammatory response observed in the pancreas and pancreatic lymph nodes (pLNs) during the natural history of type 1 diabetes (T1D). Using multicell-resolution spatial transcriptomics (ST), we profile individuals without diabetes (ND), at-risk autoantibody-positive (AAb+) individuals, and T1D donors. In the T1D pancreas, we observed global upregulation of inflammation-associated transcripts, including REG family genes, C3, SOD2, and OLFM4. In the T1D pLN, LTB was significantly upregulated within the lymphoid follicles. Using an orthogonal subcellular-resolution ST platform on an independent donor set, we identified follicular B cells as the primary source of LTB in the pLN and observed increased LTB expression in lymphocytes in insulitic lesions proximal to CCL19/CCL21-expressing endothelium. Collectively, these findings highlight lymphotoxin-β and downstream chemokine signatures in the pancreatic lymphatics as well as within the insulitic lesion, which can inform future therapeutic interventions.

Quality assessment of long read data in multisample lrRNA-seq experiments using SQANTI-reads

Genome Research · 2025-03-03 · 9 citations

SQANTI-reads leverages SQANTI3, a tool for the analysis of the quality of transcript models, to develop a read-level quality control framework for replicated long-read RNA-seq experiments. The number and distribution of reads, as well as the number and distribution of unique junction chains (transcript splicing patterns), in SQANTI3 structural categories are informative of raw data quality. Multisample visualizations of QC metrics are presented by experimental design factors to identify outliers. We introduce new metrics for (1) the identification of potentially under-annotated genes and putative novel transcripts and for (2) quantifying variation in junction donors and acceptors. We applied SQANTI-reads to two different data sets, a Drosophila developmental experiment and a multiplatform data set from the LRGASP project and demonstrate that the tool effectively reveals the impact of read coverage on data quality, and readily identifies strong and weak splicing sites.

Haplotype-Resolved Chromatin Conformation Data Reveals Relationship Between Transposable Elements and Chromosomal Pairing

Genome Biology and Evolution · 2025-11-25

Chromosomal structural changes happen when genomic stability is compromised, such as in disease or in species hybrids. In these contexts, diminished control of repetitive elements has been reported, but the reasons for this are not yet well understood. There are causal associations between repetitive elements and phenotypes such as disease progression, leading us to the hypothesis that chromosomal structure may be affected by transposable elements (TEs). In an intraspecific hybrid Drosophila melanogaster cell line (PnM), the degree of pairing among trans homologous chromosomes was affected by the presence of nearby TEs, in particular, LINE and LTR elements, such as Baggins1 or Gypsy. Chromosomal pairing was significantly lower in windows containing TEs than in windows without any TEs. Pairing was also affected by TEs in mouse, which suggests a possible general association between TEs and pairing that is highly conserved.

Multiparent recombinant inbred lines crossed to a tester provide novel insights into sources of <i>cis</i> and <i>trans</i> regulation of gene expression

Genetics · 2025-11-27

To understand the relative importance of cis and trans effects on regulation, we crossed multi-parent recombinant-inbred lines (RILs) to a common tester and measured allele-specific gene expression in the offspring. Testing the difference of allelic imbalance between two RIL × Tester crosses is a test of cis or trans, depending on the RIL alleles compared. The study design also enables to separation of two sources of trans variation, genetic and environmental, detected via interactions with cis effects. We demonstrate the effectiveness of this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster. Among the 40% of all loci that show evidence of genetic variation in cis, trans effects due to environment are detectable in 31% of loci and trans effects due to genetic background in 19%, with little overlap in sources of trans variation. The genes identified in this study are associated with genes previously reported to exhibit genetic variation in gene expression. Eleven genes in a QTL for thermotolerance, previously shown to differ in expression based on temperature, have evidence for regulation of gene expression regardless of the environment, including the cuticular protein Cpr67B, suggesting a functional role for standing variation in gene expression. This study provides a blueprint for identifying regulatory variation in gene expression, as the tester design maximizes cis variation and enables the efficient assessment of all pairs of RIL alleles relative to the tester, a much smaller study compared to the pairwise direct assessment.

Biobanks in GENETICS and G3: tackling the statistical challenges

Genetics · 2025-04-01 · 1 citations

Biobanks in GENETICS and G3: tackling the statistical challenges

G3 Genes Genomes Genetics · 2025-04-01

The promise of long-read RNA-seq: reducing bias in analyses of allele imbalance

bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14 · 1 citations

Summary Inaccurate allele and gene expression counts due to map bias and genome ambiguity lead to high false positive and false negative rates in studies of allelic imbalance. We demonstrate that long read RNA-seq and straightforward quality control measures can be used to reduce bias in allele counts in case studies from four species: Drosophila melanogaster , a diploid insect; Solanum tuberosum , an autopolyploid plant; Pongo abelii , a highly heterozygous diploid primate, and Homo sapiens . We recommend 1) mapping to a personalized genome to increase the number of allele assignments 2) tracking multimapping reads and tuning mapping parameters to ensure accurate allele and gene expression counts and 3) evaluating apparent extreme allele bias to identify errors in genome assembly and annotation. We show that these steps can be executed in a straightforward manner and recommend tools for each step.

Multiparent Recombinant Inbred lines crossed to a tester provide novel insights into sources of <i>cis</i> and <i>trans</i> regulation of gene expression

bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-09

Abstract We propose crossing multi-parent recombinant-inbred-lines (RILs) to a common tester and measuring allele specific gene expression in the offspring. Testing whether allelic imbalance between two RIL x Tester crosses is equal, is a test of cis or trans depending on the RIL alleles compared. The study design also enables to separate two sources of trans variation, genetic and environmental, detected via interactions with cis effects. Examining these components of regulatory variation, we demonstrate this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster . Among the 40% of all loci that show evidence of genetic variation in cis, trans effects due to the environment are detectable in 31% of loci and trans effects due to genetic background are detectable in 19% of loci with little overlap in sources of trans variation. The loci identified in this study are associated with loci previously reported to exhibit genetic variation in gene expression in a range of tissues and large population samples, suggesting that there is consistent variation for genetic regulation of gene expression. We show that eleven loci in a QTL for thermotolerance, previously shown to differ in expression based on temperature, have evidence for regulation of gene expression regardless of the environment, including Cpr67B, a cuticular protein suggesting a potential functional role for standing variation in gene expression. This study provides a blueprint for efficiently identifying regulatory variation in gene expression, as the tester design maximizes cis variation and enables the efficient assessment of all pairs of RIL alleles relative to the tester, a much smaller study compared to the pairwise direct assessment.

Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes

bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-24

SUMMARY This study explores the inflammatory response observed in pancreata and pancreatic lymph node (pLN) samples obtained throughout the natural history of type 1 diabetes (T1D) including non-diabetic individuals and non-diabetic autoantibody positive individuals with high susceptibility using spatial transcriptomics (ST). Integration of ST with public single-cell RNA sequencing data enabled interrogation of transcriptional alterations in T1D pathogenesis across both tissues and cellular scales. In the T1D pancreas, we observed global upregulation of multiple inflammation-associated transcripts, including regenerating islet-derived ( REG ) family genes, complement factor 3 ( C3 ), SOD2 , and OLFM4 , and highlighted cellular candidates potentially contributing to these signatures. Within the T1D pLN, we observed spatially restricted upregulation of lymphotoxin-β ( LTB ) alongside follicular dendritic cell (FDC)-associated transcripts including FDCSP , CLU , and FCER2 . Collectively, these findings highlight distinct inflammation signatures in the pancreas and regional pLN which can help inform the development of future therapeutic interventions.