Biology subjects

Ashbrook, D. G.

Publications and source records attributed to Ashbrook, D. G..

At least 19 recordsLinked to original sources

bioRxiv2026

Brain structural and genetic correlates of motor coordination and learning behaviours: modelling developmental coordination disorder

Developmental coordination disorder (DCD) is a common neurodevelopmental condition characterized by impaired motor coordination and learning, yet its neurobiological and genetic bases remain poorly understood. Here, we leverage the BXD recombinant inbred mouse panel to model the polygenic architecture of DCD and link behaviour, brain structure, and genotype. High-resolution ex vivo MRI across 14 strains revealed that DCD-like mice have modestly reduced total brain volume, with a distinct neuroanatomical profile characterized by enlarged cortical regions alongside reduced cerebellar, thalamic, and other subcortical volumes. These structural differences closely mirror findings reported in human DCD. Across strains, variation in brain structure strongly correlated with motor behaviours, with coordinated patterns linking increased cortical and decreased subcortical volumes to poorer motor coordination, while more focal associations were observed for motor learning. Multivariate analysis identified a dominant brain-behaviour axis capturing this cortical-subcortical trade-off. Quantitative trait locus (QTL) mapping revealed multiple loci influencing regional brain volumes, including a prominent locus on chromosome 12 regulating cerebellar structures, but did not identify single loci driving the main multivariate brain-behaviour relationships, consistent with a distributed genetic architecture. Together, these findings demonstrate that DCD-like motor impairments arise from coordinated alterations across distributed brain systems under polygenic control. This work establishes a translational framework linking genetic variation to brain organization and motor function, and suggests that DCD reflects the extreme of a continuous spectrum of neurobiological variation rather than a discrete condition.

neuroscience↗

bioRxiv2025

Genetic Modulation of Lifespan: Dynamic Effects, Sex Differences, and Body Weight Trade-offs

The dynamics of lifespan are shaped by DNA variants that exert effects at different ages. We have mapped genetic loci that modulate age-specific mortality using an actuarial approach. We started with an initial population of 6,438 pubescent siblings and ended with a survivorship of 559 mice that lived to at least 1100 days. Twenty-nine Vita loci dynamically modulate the mean lifespan of survivorships with strong age- and sex-specific effects. Fourteen have relatively steady effects on mortality while other loci act forcefully only early or late in life and with polarities of effects that invert. A distinct set of 19 Soma loci shape the negative correlation between weights of young adults with their life expectancies--much more strongly so in males than females. Another set of 11 Soma loci shape the positive correlation between weights at older ages with life expectancies. The Vita and Soma loci share 289 age-dependent epistatic interactions (LODs [≥]3.8) but fewer than 4% are common to both sexes. We provide two examples of how to move from maps toward potential mechanisms. Our findings provide an empirical bridge between evolutionary theories on aging and genetic and molecular causes. These loci and their interactions are key to begin to understand the impact of interventions that may extend healthy lifespan in mice and even in humans.

genetics↗

bioRxiv2025

Global dissection of the impact of Alzheimer's disease on brain architecture and behavior: High resolution MRH resolves robust regional effects

Alzheimers disease (AD) affects brain regions with remarkable heterogeneity, but the precise impact of this disease on hundreds of small cortical, subcortical, and brainstem regions remains poorly defined. Here, as a prelude to testing preclinical models to prevent AD, we systematically quantified effects of human AD mutations in APP and PSEN1 on 231 regions and comprehensively evaluated changes in volume with unprecedented resolution in genetically diverse mice as a function of sex and genetic background. We studied 34 5XFAD F1 hybrids and 23 sibling controls at 14 months, evaluating learning and memory behaviors, followed by ex vivo diffusion tensor images (DTI) at 25 {micro}m resolution. We delineated 231 regions of interest (ROIs) bilaterally with high precision. Remarkably, we found bidirectional changes: marked volume increases (up to 10%) in neocortex, hippocampus, amygdala, and sensory nuclei, contrasted with decreases in striatum, pallidum, thalamus, hypothalamus, and most fiber tracts. These opposing effects are unrelated to amyloid load and are likely to reflect temporal gradients in susceptibility of ROIs. Effects are similar in both sexes but far more prominent in females. Genetic background strongly modulates penetrance of the human mutations with the AD-BXD77 F1 type having the greatest sensitivity. Light sheet microscopy and stereological analysis of NeuN+ neurons and amyloid {beta} aggregates in 22 regions revealed up to 20% loss of cells in CA3 and in anterior and intralaminar parts of the thalamus. Volumetric changes correlated with impaired fear acquisition and memory, with cases and controls often showing opposite relations between performance and regional volumes. These findings reveal unprecedented regional heterogeneity in AD progression and suggest therapeutic efficacy may vary substantially across genetic backgrounds and between sexes.

neuroscience↗

bioRxiv2024

Epigenetic study of the long-term effects of Gulf War illness

Gulf war illness is a chronic multisymptom disorder that affects as many as many as 25-35% of the military personnel who were sent to the Persian Gulf war in 1991. The illness has many debilitating symptoms, including cognitive problems, gastrointestinal symptoms, and musculoskeletal pain. Those so afflicted have been sick for more than 30 years and, therefore, it has become imperative to understand the etiology and then produce treatments to ease the symptoms. We hypothesized that the length of the disease was reflected in epigenetic modification of possibly several genes related to the symptoms. We subjected male and female mice from 11 BXD strains to combined corticosterone and the sarin surrogate, diisopropylfluorophosphate, to emulate the physiological stress of war and the potential exposures to organophosphate pesticides and nerve agent in theater. Three hundred days after treatment, we analyzed the animals DNA for genome-wide methylation by MBD-seq. The analysis revealed 20 methylated genes, notably Eif2B5, that regulates myelin production. Loss of myelin with accompanying musculoskeletal pain is a major symptom of Gulf War illness. Our work demonstrates multiple genes were methylated by exposure to OPs and glucocorticoids. These genes point to biochemical mechanisms that may be targets for therapeutic intervention.

pharmacology and toxicology↗

bioRxiv2024

Creating a biomedical knowledge base by addressing GPT inaccurate responses and benchmarking context

We created GNQA, a generative pre-trained transformer (GPT) knowledge base driven by a performant retrieval augmented generation (RAG) with a focus on aging, dementia, Alzheimers and diabetes. We uploaded a corpus of three thousand peer reviewed publications on these topics into the RAG. To address concerns about inaccurate responses and GPT hallucinations, we implemented a context provenance tracking mechanism that enables researchers to validate responses against the original material and to get references to the original papers. To assess the effectiveness of contextual information we collected evaluations and feedback from both domain expert users and citizen scientists on the relevance of GPT responses. A key innovation of our study is automated evaluation by way of a RAG assessment system (RAGAS). RAGAS combines human expert assessment with AI-driven evaluation to measure the effectiveness of RAG systems. When evaluating the responses to their questions, human respondents give a "thumbs-up" 76% of the time. Meanwhile, RAGAS scores 90% on answer relevance on questions posed by experts. And when GPT-generates questions, RAGAS scores 74% on answer relevance. With RAGAS we created a benchmark that can be used to continuously assess the performance of our knowledge base. Full GNQA functionality is embedded in the free GeneNetwork.org web service, an open-source system containing over 25 years of experimental data on model organisms and human. The code developed for this study is published under a free and open-source software license at https://git.genenetwork.org/gn-ai/tree/README.md.

scientific communication and education↗

bioRxiv2024

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Breast cancer (BC) is the most common cancer and the second cause of death in US women. Our lack of understanding of how genetic variants affect molecular mechanisms that mediate BC aggression poses a substantial obstacle to advancements in cancer diagnosis and therapy. To examine genetic variants on BC traits, a novel murine model was created with robust phenotypic and genomic variation. The FVB C3(1)-T-antigen ("C3Tag") mouse develops spontaneous tumors in the mammary glands of female mice with a mean latency of 4-5 months of age. This genetically engineered mouse model (GEMM) is well established to resemble human basal-like TNBC. TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family - the largest and best characterized genetic reference population. The new model is termed "BXD-BC" and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. We hypothesized that examination of BXD-BC GEMMs will enable the identification of susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple BC phenotypes. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. Interestingly, 2 BXD-BC strains never developed tumors out to 1 year of age. Thus, BXD-BC strains demonstrate variance in cancer susceptibility and progression compared to the parent C3Tag GEMM, indicating the presence of genetic modifiers. Through an unbiased systematic quantification of breast cancer severity across BXD-BC hybrids, we identified several significant quantitative trait loci (QTL) and candidate genes for specific tumor traits. In combination with public human GWAS datasets, we defined syntenic regions, candidate genes, and underlying networks through cross-species systems genetics analyses to demonstrate the translational validity of conserved, biologically relevant, and targetable candidates. Our findings suggest conserved candidates predicting TNBC patient survival. In sum, the BXD-BC resource is an innovative, reliable, and robust preclinical model that reflects robust genetic heterogeneity. Using cutting edge systems genetics, we have identified genetic modifiers of BC phenotypic variation that could be targeted to advance therapeutic limitations or as biomarkers of risk or response to therapy.

genetics↗

bioRxiv2023

Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1

In aged humans and mice, aggregates of hypobranched glycogen molecules called polyglucosan bodies (PGBs) accumulate in hippocampal astrocytes. PGBs are known to drive cognitive decline in neurological diseases but remain largely unstudied in the context of typical brain aging. Here, we show that PGBs arise in autophagy-dysregulated astrocytes of the aged C57BL/6J mouse hippocampus. To map the genetic cause of age-related PGB accumulation, we quantified PGB burden in 32 fully sequenced BXD-recombinant inbred mouse strains, which display a 400-fold variation in hippocampal PGB burden at 16-18 months of age. A major modifier locus was mapped to chromosome 1 at 72-75 Mb, which we defined as the Pgb1 locus. To evaluate candidate genes and downstream mechanisms by which Pgb1 controls the aggregation of glycogen, extensive hippocampal transcriptomic and proteomic datasets were produced for aged mice of the BXD family. We utilized these datasets to identify Smarcal1 and Usp37 as potential regulators of PGB accumulation. To assess the effect of PGB burden on age-related cognitive decline, we performed phenome-wide association scans, transcriptomic analyses as well as conditioned fear memory and Y-maze testing. Importantly, we did not find any evidence suggesting a negative impact of PGBs on cognition. Taken together, our study demonstrates that the Pgb1 locus controls glycogen aggregation in astrocytes of the aged hippocampus without affecting age-related cognitive decline.

genetics↗

bioRxiv2023

GenomeMUSter mouse genetic variation service enables multi-trait, multi-population data integration and analyses

Hundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait - variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web- and programmatically-accessible data service called GenomeMUSter (https://muster.jax.org), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

genetics↗

bioRxiv2023

RNA Strain-Match: A tool for matching single-nucleus, single-cell, or bulk RNA-sequencing alignment data to its corresponding genotype

When next generation sequencing is performed in large batches, there are several stages at which samples can be swapped or mislabeled. It is therefore helpful, when possible, to integrate measures into analysis pipelines to confirm that samples match their assigned metadata. Here, we introduce RNA Strain-Match (GitHub: https://github.com/jon-willcox/RNA-strain-match), a quality control tool developed to match RNA data in the form of sequence alignment files (i.e. SAM or BAM files) to their corresponding genotype without the use of an RNA variant call format file. We successfully used RNA Strain-Match in tandem with assessment of markers for sex and transgene status to identify and correct sample mismatches in 50/379 samples (13%) from two distinct recombinant inbred mouse models (BXD and Collaborative Cross). We believe this tool will be beneficial to any research group working with similar data.

bioinformatics↗

bioRxiv2023

Building pangenome graphs

Pangenome graphs can represent all variation between multiple reference genomes, but current approaches to build them exclude complex sequences or are based upon a single reference. In response, we developed the PanGenome Graph Builder (PGGB), a pipeline for constructing pangenome graphs without bias or exclusion. PGGB uses all-to-all alignments to build a variation graph in which we can identify variation, measure conservation, detect recombination events, and infer phylogenetic relationships.

bioinformatics↗

bioRxiv2023

Genome-wide screen identifies host loci that modulate M. tuberculosis fitness in immunodivergent mice

Genetic differences among mammalian hosts and Mycobacterium tuberculosis (Mtb) strains determine diverse tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host- pathogen interactions. To identify host and pathogen genetic determinants of Mtb pathogenesis, we infected members of the BXD family of mouse strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb-resistant C57BL/6J (B6 or B) and Mtb-susceptible DBA/2J (D2 or D) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters for "endophenotypes", each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted QTL mapping of these bacterial fitness endophenotypes and identified 140 host-pathogen quantitative trait loci (hpQTL). We identified a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes; Rv0127 (mak), Rv0359 (rip2), Rv0955 (perM), and Rv3849 (espR). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB.

genetics↗

bioRxiv2022

Developmental Coordination Disorder: What Can We Learn From Recombinant Inbred Mice Using Motor Learning Tasks and Quantitative Trait Locus Analysis

Developmental Coordination Disorder (DCD) is a motor skills disorder that affects 5-6% of all school-aged children. There is an indication that DCD has an underlying genetic component due to its high heritability. Therefore, we we have explored the use of a recombinant inbred family of mice known as the BXD panel to understand the genetic basis of complex traits (i.e., motor learning) through identification of Quantitative Trait Loci (QTLs). The overall aim of this study was to utilize the QTL approach to evaluate the genome-to-phenome correlation in BXD strains of mice in order to to better understanding the human presentation of DCD. Results in this current study indicate there is a spectrum of motor learning in the pre-selected BXD strains of mice with a spectrum between high and low learning capabilities. Five lines - BXD15, BXD27, BXD28, BXD75, and BXD86 - exhibited the most DCD-like phenotype, when compared to other BXD lines of interest. The results indicate that BXD15 and BXD75 struggled primarily with gross motor skills, BXD28 primarily had difficulties with fine motor skills, and BXD27 and BXD28 lines struggled with both fine and gross motor skills. The functional roles of significant QTL genes were assessed in relation to DCD-like behavior. Only Rab3a (Ras-related protein Rab-3A) emerged as a best candidate gene for the horizontal ladder rung task. This gene is found to be associated with brain and skeletal muscle development. This is the first study to specifically examine the genetic linkage of DCD using BXD lines of mice.

neuroscience↗

bioRxiv2022

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD family of recombinant inbred mice were developed by crossing and inbreeding progeny of C57BL/6J and DBA/2J strains. This family is the largest and most extensively phenotyped mammalian experimental genetic resource. Although used in genetics for 52 years, we do not yet have comprehensive data on DNA variants segregating in the BXDs. Using linked-read whole-genome sequencing, we sequenced 152 members of the family at about 40X coverage and quantified most variants. We identified 6.25 million polymorphism segregating at a near-optimal minor allele frequency of 0.42. We also defined two other major variants: strain-specific de novo singleton mutations and epoch-specific de novo polymorphism shared among subfamilies of BXDs. We quantified per-generation mutation rates of de novo variants and demonstrate how founder-derived, strain-specific, and epoch-specific variants can be analyzed jointly to model genome-phenome causality. This integration enables forward and reverse genetics at scale, rapid production of any of more than 10,000 diallel F1 hybrid progeny to test predictions across diverse environments or treatments. Combined with five decades of phenome data, the BXD family and F1 hybrids are a major resource for systems genetics and experimental precision medicine.

genomics↗

bioRxiv2022

Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS finding

Exploring the molecular genetic cascades responsible for behavioral responses to opioids can improve our understanding of drug use initiation. We generated high-precision time-series data for 105 morphine-and naloxone-related traits across [~]700 young adult BXD mice (64 diverse strains and both sexes) for 3 hours after a single morphine injection. Variations in responses were mapped using high-precision genome sequencing-based genotypes. The initial locomotor responses to morphine mapped precisely to the {micro} opioid receptor gene (Oprm1) on chromosome (Chr) 10 with a peak linkage of 12.4 (-logP, genome-wide significance level is approximately 3.8). The B allele inherited from C57BL/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of opioid-induced locomotion emerged after approximately 100 min. This locus, also associated with a high B allele, was located on Chr 16 with peak linkage of 10.6 (-logP) in females. This locus included only one compelling candidate, fibroblast growth factor 12 (Fgf12), a 600 Kb gene that controls sodium current kinetics at the axon hillock. A strong and transient epistatic interaction existed between the Oprm1 and Fgf12 loci during a short time window (45-75 min). The combination of a B haplotype at Oprm1 with a D haplotype from DBA/2J at Fgf12 was associated with unusually high activity. In a complementary study in heterogeneous stock rats, we demonstrated that Oprm1 and Fgf12 were co-expressed in one specific subtype of Drd1+ medium spiny neuron. A Bayesian network analysis supported an Oprm1-to-Fgf12 network that involves a MAP kinase cascade that modulates FGF12 phosphorylation and locomotor activation. OPRM1 and FGF12 networks in human GWAS data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.

genetics↗

bioRxiv2022

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements characterized by repeated units of 1 or more nucleotides. We leveraged whole genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family derived from C57BL/6J and DBA/2J mice to study the effects of genetic background on genome-wide patterns of new mutations at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and identified a locus on chromosome 13 associated with the propensity of STRs to expand. Several dozen genes lie in the QTL region, including Msh3, a known modifier of STR stability at pathogenic repeat expansions in mice and humans. Detailed analysis of the locus revealed a cluster of variants near the 5 end of Msh3, including multiple protein-coding variants within the DNA mismatch recognition domain of MSH3, and a retrotransposon insertion overlapping an annotated exon. Additionally, gene expression analysis demonstrates co-localization of this QTL with expression QTLs for multiple nearby genes, including Msh3. Our results suggest a novel role for Msh3 in regulating genome-wide patterns of germline STR mutations and demonstrate that inherited genetic variation can contribute to variability in accumulation of new mutations across individuals.

genomics↗

bioRxiv2021

Old data and friends improve with age: Advancements with the updated tools of GeneNetwork

Understanding gene-by-environment interactions is important across biology, particularly behaviour. Families of isogenic strains are excellently placed, as the same genome can be tested in multiple environments. The BXDs recent expansion to 140 strains makes them the largest family of murine isogenic genomes, and therefore give great power to detect QTL. Indefinite reproducible genometypes can be leveraged; old data can be reanalysed with emerging tools to produce novel biological insights. To highlight the importance of reanalyses, we obtained drug- and behavioural-phenotypes from Philip et al. 2010, and reanalysed their data with new genotypes from sequencing, and new models (GEMMA and R/qtl2). We discover QTL on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We narrowed down the candidate genes based on their ability to alter gene expression and/or protein function, using cis-eQTL analysis, and variants predicted to be deleterious. Co-expression analysis ( gene friends) and human PheWAS were used to further narrow candidates. Prominent candidate genes include: Slitrk6 in a Chr 14 QTL for locomotion in the center of an open field, we show to be part of a coexpression network involved in voluntary movement, and association with neuropsychiatric phenotypes in PheWAS; and Cdk14, one of only 3 genes in a Chr 5 QTL for handling induced convulsions after ethanol treatment, that is regulated by the anticonvulsant drug valproic acid. By using families of isogenic strains, we can reuse and reanalyse data to discover novel and highly plausible candidate genes involved in response to the environment.

genomics↗

bioRxiv2021

A wild-derived antimutator drives germline mutation spectrum differences in a genetically diverse murine family

Summary ParagraphAlthough germline mutation rates and spectra can vary within and between species, genetic modifiers of these traits have long eluded detection. In this study, we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory mouse strains C57BL/6J (B) and DBA/2J (D). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes. We show that mice inheriting D haplotypes at a quantitative trait locus (QTL) on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily due to the activity of a C>A-dominated mutational signature known as SBS18. The B and D QTL haplotypes encode different alleles of the DNA repair gene Mutyh, which underlies the heritable colorectal cancer syndrome in which SBS18 was first identified. The B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.

genetics↗

bioRxiv2020

GeneNetwork: a continuously updated tool for systems genetics analyses

GeneNetwork and its earlier iteration, WebQTL, have now been an important database and toolkit for quantitative trait genetics research for two decades. Recent improvements to GeneNetwork have reinvigorated it, including the addition of data from 10 species, multi-omics analysis, updated code, and new tools. The new GeneNetwork is now an exciting resource for predictive medicine and systems genetics, which is constantly being maintained and improved. Here, we give a brief overview of the process for carrying out some of the most common functions on GeneNetwork, as a gateway to deeper analyses, demonstrating how a small number of plausible candidate genes can be found for a typical immune phenotype.

genomics↗