Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population.

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations.

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into ß-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: (1) 8 mM glucose; (2) 8 mM glucose plus amino acids; (3) 8 mM glucose, amino acids, plus 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate ß-cell function, α- to ß-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominate novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/ß hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin.

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes α/ß-hydrolase domain 2 (Abhd2), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2. The Abhd2KO mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.

Expression of tau and phosphorylated tau in the brain of normal and hemiparkinsonian rhesus macaques.

Tau is a neuronal protein involved in microtubule stabilization and intracellular vesicle transport in axons. In neurodegenerative disorders termed "tauopathies," like Alzheimer's and Parkinson's disease, tau becomes hyperphosphorylated and forms intracellular inclusions. Rhesus macaques are widely used for studying ageing processes and modeling neurodegenerative disorders, yet little is known about endogenous tau expression in their brains. In this study, immunohistochemical methods were used to map and characterize total tau, 3R- and 4R-tau isoforms, and phosphorylated tau (pThr231-tau and pSer202/Thr205-tau/AT8) expression bilaterally in 16 brain regions of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian adult rhesus macaques. Tau-immunoreactivity (-ir), including both 3R and 4R isoforms, was observed throughout the brain, with varying regional intensities. The anterior cingulate cortex, entorhinal cortex, and hippocampus displayed the most robust tau-ir, while the subthalamic nucleus and white matter regions had minimal expression. Tau was present in neurons of gray matter regions; it was preferentially observed in fibers of the globus pallidus and substantia nigra and in cell bodies of the thalamus and subthalamic nucleus. In white matter regions, tau was abundantly present in oligodendrocytes. Additionally, neuronal pThr231-tau-ir was abundant in all brain regions, but not AT8-ir. Differences in regional and intracellular protein expression were not detected between control subjects and both brain hemispheres of MPTP-treated animals. Specifically, tau-ir in the substantia nigra of all subjects colocalized with GABAergic neurons. Overall, this report provides an in-depth characterization of tau expression in the rhesus macaque brain to facilitate future investigations for understanding and modeling tau pathology in this species.

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/ß hydrolase domain 2 ( Abhd2 ) as an enzyme that metabolizes phosphatidylcholine and cardiolipin.

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes α/ß-hydrolase domain 2 ( Abhd2 ), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2 . The Abhd2 KO mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2 KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.

Real-time estimation and forecasting of COVID-19 cases and hospitalizations in Wisconsin HERC regions for public health decision making processes.

BACKGROUND: The spread of the COVID-19 (SARS-CoV-2) and the surging number of cases across the United States have resulted in full hospitals and exhausted health care workers. Limited availability and questionable reliability of the data make outbreak prediction and resource planning difficult. Any estimates or forecasts are subject to high uncertainty and low accuracy to measure such components. The aim of this study is to apply, automate, and assess a Bayesian time series model for the real-time estimation and forecasting of COVID-19 cases and number of hospitalizations in Wisconsin healthcare emergency readiness coalition (HERC) regions. METHODS: This study makes use of the publicly available Wisconsin COVID-19 historical data by county. Cases and effective time-varying reproduction number [Formula: see text] by the HERC region over time are estimated using Bayesian latent variable models. Hospitalizations are estimated by the HERC region over time using a Bayesian regression model. Cases, effective Rt, and hospitalizations are forecasted over a 1-day, 3-day, and 7-day time horizon using the last 28 days of data, and the 20%, 50%, and 90% Bayesian credible intervals of the forecasts are calculated. The frequentist coverage probability is compared to the Bayesian credible level to evaluate performance. RESULTS: For cases and effective [Formula: see text], all three time horizons outperform the three credible levels of the forecast. For hospitalizations, all three time horizons outperform the 20% and 50% credible intervals of the forecast. On the contrary, the 1-day and 3-day periods underperform the 90% credible intervals. Questions about uncertainty quantification should be re-calculated using the frequentist coverage probability of the Bayesian credible interval based on observed data for all three metrics. CONCLUSIONS: We present an approach to automate the real-time estimation and forecasting of cases and hospitalizations and corresponding uncertainty using publicly available data. The models were able to infer short-term trends consistent with reported values at the HERC region level. Additionally, the models were able to accurately forecast and estimate the uncertainty of the measurements. This study can help identify the most affected regions and major outbreaks in the near future. The workflow can be adapted to other geographic regions, states, and even countries where decision-making processes are supported in real-time by the proposed modeling system.

pH-Responsive Polymer Nanoparticles for Efficient Delivery of Cas9 Ribonucleoprotein With or Without Donor DNA.

Clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) may offer new therapeutics for genetic diseases through gene disruption via nonhomologous end joining (NHEJ) or gene correction via homology-directed repair (HDR). However, clinical translation of CRISPR technology is limited by the lack of safe and efficient delivery systems. Here, facilely fabricated pH-responsive polymer nanoparticles capable of safely and efficiently delivering Cas9 ribonucleoprotein alone (termed NHEJ-NP, diameter = 29.4 nm), or together with donor DNA (termed HDR-NP, diameter = 33.3 nm) are reported. Moreover, intravenously, intratracheally, and intramuscularly injected NHEJ-NP induces efficient gene editing in mouse liver, lung, and skeletal muscle, respectively. Intramuscularly injected HDR-NP also leads to muscle strength recovery in a Duchenne muscular dystrophy mouse model. NHEJ-NP and HDR-NP possess many desirable properties including high payload loading content, small and uniform sizes, high editing efficiency, good biocompatibility, low immunogenicity, and ease of production, storage, and transport, making them great interest for various genome editing applications with clinical potentials.

Interventions to Disrupt Coronavirus Disease Transmission at a University, Wisconsin, USA, August-October 2020.

University settings have demonstrated potential for coronavirus disease (COVID-19) outbreaks; they combine congregate living, substantial social activity, and a young population predisposed to mild illness. Using genomic and epidemiologic data, we describe a COVID-19 outbreak at the University of Wisconsin-Madison, Madison, Wisconsin, USA. During August-October 2020, a total of 3,485 students, including 856/6,162 students living in dormitories, tested positive. Case counts began rising during move-in week, August 25-31, 2020, then rose rapidly during September 1-11, 2020. The university initiated multiple prevention efforts, including quarantining 2 dormitories; a subsequent decline in cases was observed. Genomic surveillance of cases from Dane County, in which the university is located, did not find evidence of transmission from a large cluster of cases in the 2 quarantined dorms during the outbreak. Coordinated implementation of prevention measures can reduce COVID-19 spread in university settings and may limit spillover to the surrounding community.

Association of Mobile Phone Location Data Indications of Travel and Stay-at-Home Mandates With COVID-19 Infection Rates in the US.

Importance: A stay-at-home social distancing mandate is a key nonpharmacological measure to reduce the transmission rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but a high rate of adherence is needed. Objective: To examine the association between the rate of human mobility changes and the rate of confirmed cases of SARS-CoV-2 infection. Design, Setting, and Participants: This cross-sectional study used daily travel distance and home dwell time derived from millions of anonymous mobile phone location data from March 11 to April 10, 2020, provided by the Descartes Labs and SafeGraph to quantify the degree to which social distancing mandates were followed in the 50 US states and District of Columbia and the association of mobility changes with rates of coronavirus disease 2019 (COVID-19) cases. Exposure: State-level stay-at-home orders during the COVID-19 pandemic. Main Outcomes and Measures: The main outcome was the association of state-specific rates of COVID-19 confirmed cases with the change rates of median travel distance and median home dwell time of anonymous mobile phone users. The increase rates are measured by the exponent in curve fitting of the COVID-19 cumulative confirmed cases, while the mobility change (increase or decrease) rates were measured by the slope coefficient in curve fitting of median travel distance and median home dwell time for each state. Results: Data from more than 45 million anonymous mobile phone devices were analyzed. The correlation between the COVID-19 increase rate and travel distance decrease rate was -0.586 (95% CI, -0.742 to -0.370) and the correlation between COVID-19 increase rate and home dwell time increase rate was 0.526 (95% CI, 0.293 to 0.700). Increases in state-specific doubling time of total cases ranged from 1.0 to 6.9 days (median [interquartile range], 2.7 [2.3-3.3] days) before stay-at-home orders were enacted to 3.7 to 30.3 days (median [interquartile range], 6.0 [4.8-7.1] days) after stay-at-home social distancing orders were put in place, consistent with pandemic modeling results. Conclusions and Relevance: These findings suggest that stay-at-home social distancing mandates, when they were followed by measurable mobility changes, were associated with reduction in COVID-19 spread. These results come at a particularly critical period when US states are beginning to relax social distancing policies and reopen their economies. These findings support the efficacy of social distancing and could help inform future implementation of social distancing policies should they need to be reinstated during later periods of COVID-19 reemergence.

Reconstruction of Networks with Direct and Indirect Genetic Effects.

Genetic variance of a phenotypic trait can originate from direct genetic effects, or from indirect effects, i.e., through genetic effects on other traits, affecting the trait of interest. This distinction is often of great importance, for example, when trying to improve crop yield and simultaneously control plant height. As suggested by Sewall Wright, assessing contributions of direct and indirect effects requires knowledge of (1) the presence or absence of direct genetic effects on each trait, and (2) the functional relationships between the traits. Because experimental validation of such relationships is often unfeasible, it is increasingly common to reconstruct them using causal inference methods. However, most current methods require all genetic variance to be explained by a small number of quantitative trait loci (QTL) with fixed effects. Only a few authors have considered the "missing heritability" case, where contributions of many undetectable QTL are modeled with random effects. Usually, these are treated as nuisance terms that need to be eliminated by taking residuals from a multi-trait mixed model (MTM). But fitting such an MTM is challenging, and it is impossible to infer the presence of direct genetic effects. Here, we propose an alternative strategy, where genetic effects are formally included in the graph. This has important advantages: (1) genetic effects can be directly incorporated in causal inference, implemented via our PCgen algorithm, which can analyze many more traits; and (2) we can test the existence of direct genetic effects, and improve the orientation of edges between traits. Finally, we show that reconstruction is much more accurate if individual plant or plot data are used, instead of genotypic means. We have implemented the PCgen-algorithm in the R-package pcgen.

Genetic determinants of gut microbiota composition and bile acid profiles in mice.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.

Gene loci associated with insulin secretion in islets from non-diabetic mice.

Genetic susceptibility to type 2 diabetes is primarily due to ß-cell dysfunction. However, a genetic study to directly interrogate ß-cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged >1,000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion QTL from mouse are associated with diabetes-related SNPs in human genome-wide association studies. We report on three genes, Ptpn18, Hunk and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These three genes encode a non-receptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in non-diabetic individuals.

Testing Pleiotropy vs. Separate QTL in Multiparental Populations.

The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides important insight into the underlying mechanism and can assist planning for subsequent experiments. We extend the method of Jiang and Zeng (1995), for testing pleiotropy with a pair of traits, to the case of more than two alleles. We also incorporate polygenic random effects to account for population structure. We use a parametric bootstrap to determine statistical significance. We apply our methods to a behavioral genetics data set from Diversity Outbred mice. Our methods have been incorporated into the R package qtl2pleio.

qtl2pleio: Testing pleiotropy vs. separate QTL in multiparental populations.

Modern quantitative trait locus (QTL) studies in multiparental populations offer opportunities to identify causal genes for thousands of clinical and molecular traits. Traditional analyses examine each trait by itself. However, to fully leverage this vast number of measured traits, the systems genetics community needs statistical tools to analyze multiple traits simultaneously (Jiang & Zeng, 1995; Korol, Ronin, & Kirzhner, 1995). A test of pleiotropy vs. separate QTL is one such tool that will aid dissection of complex trait genetics and enhance understanding of genetic architecture.

R/qtl2: Software for Mapping Quantitative Trait Loci with High-Dimensional Data and Multiparent Populations.

R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely used R/qtl software package to include multiparent populations derived from more than two founder strains, such as the Collaborative Cross and Diversity Outbred mice, heterogeneous stocks, and MAGIC plant populations. R/qtl2 is designed to handle modern high-density genotyping data and high-dimensional molecular phenotypes, including gene expression and proteomics. R/qtl2 includes the ability to perform genome scans using a linear mixed model to account for population structure, and also includes features to impute SNPs based on founder strain genomes and to carry out association mapping. The R/qtl2 software provides all of the basic features needed for QTL mapping, including graphical displays and summary reports, and it can be extended through the creation of add-on packages. R/qtl2, which is free and open source software written in the R and C++ programming languages, comes with a test framework.

Genetic Drivers of Pancreatic Islet Function.

The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45% kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression QTL. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for ß-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the ß-cell population. A module enriched in transcripts associated with branched-chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse and those found in human populations, and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.

Dissecting the Genetic Architecture of Shoot Growth in Carrot (Daucus carota L.) Using a Diallel Mating Design.

Crop establishment in carrot (Daucus carota L.) is limited by slow seedling growth and delayed canopy closure, resulting in high management costs for weed control. Varieties with improved growth habit (i.e., larger canopy and increased shoot biomass) may help mitigate weed control, but the underlying genetics of these traits in carrot is unknown. This project used a diallel mating design coupled with recent Bayesian analytical methods to determine the genetic basis of carrot shoot growth. Six diverse carrot inbred lines with variable shoot size were crossed in WI in 2014. F1 hybrids, reciprocal crosses, and parental selfs were grown in a randomized complete block design with two blocks in WI (2015) and CA (2015, 2016). Measurements included canopy height, canopy width, shoot biomass, and root biomass. General and specific combining abilities were estimated using Griffing's Model I, which is a common analysis for plant breeding experiments. In parallel, additive, inbred, cross-specific, and maternal effects were estimated from a Bayesian mixed model, which is robust to dealing with data imbalance and outliers. Both additive and nonadditive effects significantly influenced shoot traits, with nonadditive effects playing a larger role early in the growing season, when weed control is most critical. Results suggest the presence of heritable variation and thus potential for improvement of these phenotypes in carrot. In addition, results present evidence of heterosis for root biomass, which is a major component of carrot yield.

Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes.

Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

The Transcription Factor Nfatc2 Regulates ß-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2. As all but 9 of these genes are not physically located on Chr 2, linkage to Chr 2 suggests a genomic factor(s) located on Chr 2 regulates their expression in trans. The transcription factor Nfatc2 is physically located on Chr 2 and its expression demonstrates cis linkage; i.e., its expression maps to itself. When conditioned on the expression of Nfatc2, linkage for the T2D-associated genes was greatly diminished, supporting Nfatc2 as a driver of their expression. Plasma insulin also showed linkage to the same broad region on Chr 2. Overexpression of a constitutively active (ca) form of Nfatc2 induced ß-cell proliferation in mouse and human islets, and transcriptionally regulated more than half of the T2D-associated genes. Overexpression of either ca-Nfatc2 or ca-Nfatc1 in mouse islets enhanced insulin secretion, whereas only ca-Nfatc2 was able to promote ß-cell proliferation, suggesting distinct molecular pathways mediating insulin secretion vs. ß-cell proliferation are regulated by NFAT. Our results suggest that many of the T2D-associated genes are downstream transcriptional targets of NFAT, and may act coordinately in a pathway through which NFAT regulates ß-cell proliferation in both mouse and human islets.

Fine Mapping of a QTL Associated with Kernel Row Number on Chromosome 1 of Maize.

The genetic factors underlying changes in ear morphology, and particularly the inheritance of kernel row number (KRN), have been broadly investigated in diverse mapping populations in maize (Zea mays L.). In this study, we mapped a region on the long arm of chromosome 1 containing a QTL for KRN. This work was performed using a set of recombinant chromosome nearly isogenic lines (RCNILs) derived from a BC2S3 population produced using the inbred maize line W22 and teosinte (Zea mays ssp. parviglumis) as the parents. A set of 48 RCNILs was evaluated in the field during the summer of 2013 in order to perform the mapping. A QTL for KRN was found that explained approximately 51% of the phenotypic variance and had a 1.5-LOD confidence interval of 203 kb. Seven genes are described in this interval. One of these candidate genes may have been the target of domestication processes in maize and contributed to the shift from two kernel row ears in teosinte to a highly polystichous ear in maize.