Biology subjects

Lawson, H. A.

Publications and source records attributed to Lawson, H. A..

7 recordsLinked to original sources

bioRxiv2026

Leveraging Human Pangenome for Improved Somatic Variant Detection

Somatic variant detection is technically challenging due to low variant allele fractions, the confounding presence of germline variation, and reference bias. Linear references such as GRCh38 miss sample-specific variation, causing misalignments and incorrect variant calls. Although telomere-to-telomere donor-specific assemblies (DSAs) accurately represent individual genomes, their application is limited by cost and technical barriers. Alternatively, the graph-based human pangenome provides a scalable framework to improve read alignment and perform genome inference. Here, we benchmarked somatic variant detection using GRCh38, graph-based pangenomes, and pangenome-inferred DSAs with a HapMap mixture dataset and the COLO829 melanoma cell line. Pangenome-guided alignment improves read mapping and somatic variant calling accuracy. Furthermore, personalized pangenomes partially reconstruct donor-specific genomic content, improving accuracy, reducing germline contamination, and enabling detection of events in loci absent or poorly represented in GRCh38. These findings demonstrate that graph-based and personalized pangenomes are effective strategies for enhancing somatic variant detection compared with GRCh38.

genomics↗

bioRxiv2021

Parent-of-origin effects propagate through networks to shape metabolic traits

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological diseases. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat and F2r are negatively correlated in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.

genomics↗

bioRxiv2021

Integrated transcriptomics identifies β-cell subpopulations and genetic networks associated with obesity and glycemic control in SM/J mice

Understanding how heterogeneous {beta}-cell function and stress response impact diabetic etiology is imperative for therapy development. Standard single-cell RNA sequencing analysis illuminates some genetic underpinnings driving heterogeneity, but new strategies are required to capture information lost due to technical limitations. Here, we integrate pancreatic islet single-cell and bulk RNA sequencing data to identify {beta}-cell subpopulations based on gene expression and characterize genetic networks associated with {beta}-cell function in high- and low-fat fed male and female SM/J mice at 20 and 30wks of age. Previous studies have shown that high-fat fed SM/J mice resolve glycemic dysfunction between 20 and 30wks. We identify 4 {beta}-cell subpopulations associated with insulin secretion, hypoxia response, cell polarity, and stress response. Relative proportions of these cells are influenced by age, sex, and diet. Network analysis identifies fatty acid metabolism and {beta}-cell physiology gene expression modules associated with the hyperglycemic-obese state. We identify subtype-specific expression of Pdyn and Fam151a as candidate regulators of genetic pathways associated with {beta}-cell function in obesity. In sum, this study uses a novel data integration method to explore how {beta}-cells respond to obesity and glycemic stress, helping to define the relationship between {beta}-cell heterogeneity and diabetes, and shedding light on novel genetic pathways with therapeutic potential.

genomics↗

bioRxiv2020

TRAP-based allelic translation efficiency imbalance analysis to identify genetic regulation of ribosome occupancy in specific cell types in vivo.

The alteration of gene expression due to variations in the sequences of transcriptional regulatory elements has been a focus of substantial inquiry in humans and model organisms. However, less is known about the extent to which natural variation contributes to post-transcriptional regulation. Allelic Expression Imbalance (AEI) is a classical approach for studying the association of specific haplotypes with relative changes in transcript abundance. Here, we piloted a new TRAP based approach to associate genetic variation with transcript occupancy on ribosomes in specific cell types, to determine if it will allow examination of Allelic Translation Imbalance (ATI), and Allelic Translation Efficiency Imbalance, using as a test case mouse astrocytes in vivo. We show that most changes of the mRNA levels on ribosomes were reflected in transcript abundance, though [~]1.5% of transcripts have variants that clearly alter loading onto ribosomes orthogonally to transcript levels. These variants were often in conserved residues and altered sequences known to regulate translation such as upstream ORFs, PolyA sites, and predicted miRNA binding sites. Such variants were also common in transcripts showing altered abundance, suggesting some genetic regulation of gene expression may function through post-transcriptional mechanisms. Overall, our work shows that naturally occurring genetic variants can impact ribosome occupancy in astrocytes in vivo and suggests that mechanisms may also play a role in genetic contributions to disease.

genetics↗

bioRxiv2020

Spontaneous restoration of functional β-cell mass in obese SM/J mice

Maintenance of functional {beta}-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause {beta}-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study {beta}-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and {beta}-cell function during SM/Js diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase {beta}-cell mass but not -cell mass. Obese SM/J mice do not show elevated {beta}-cell mitotic index, but rather elevated -cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that {beta}-cell mass expansion and improved {beta}-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional {beta}-cell mass can be recovered in the context of obesity.

physiology↗

bioRxiv2019

Natural brown adipose expansion and remission of hyperglycemia in obese SM/J mice

Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a healthier expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, and transcriptomic changes that occur during the unique brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity. Significance StatementSome obese individuals maintain normal glycemic control. Despite being obese, these individuals have low risk for metabolic complications, including type-II diabetes. If we better understood why some obese people maintain normoglycemia then we might develop new approaches for treating metabolic complications associated with obesity. However, the causative factors underlying glycemic control in obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity.

physiology↗

bioRxiv2019

Epistatic Networks Associated with Parent-of-Origin Effects on Metabolic Traits

Parent-of-origin effects (POE) are unexpectedly common in complex traits, including metabolic and neurological diseases. POE can also be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific POE on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these POE phenomena. Here, we use a simple yet powerful F1 reciprocal cross model to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes. Male and female mice from a F1 reciprocal cross of LG/J and SM/J strains were fed either high or low fat diets. We generated expression profiles from three metabolically-relevant tissues: hypothalamus, white adipose, and liver. We identified two classes of parent-of-origin expression biases: genes showing parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross. POE patterns of both gene classes are highly tissue-and context-specific, sometimes occurring only in one sex and/or diet cohort in a particular tissue. We then constructed tissue-specific interaction networks among genes from these two classes of POE. A key subset of gene pairs show significant epistasis in the F16 LG/J x SM/J advanced intercross data in cases where the biallelic gene fell within a previously-identified metabolic POE QTL interval. We highlight one such interaction in adipose, between Nnat and Mogat1, which associates with POE on multiple adiposity traits. Both genes localize to the endoplasmic reticulum of adipocytes and play a role in adipogenesis. Additionally, expression of both genes is significantly correlated in human visceral adipose tissue. The genes and networks we present here represent a set of actionable interacting candidates that can be probed to further identify the machinery driving POE on complex traits.

systems biology↗