Biology subjects

Barsh, G. S.

Publications and source records attributed to Barsh, G. S..

8 recordsLinked to original sources

bioRxiv2026

Transmembrane aminopeptidase Q (Taqpep) is a common mechanism in the establishment of periodic patterning in skin and intestine

Periodic patterns are a frequent motif in biology that occurs across diverse tissues and species. In mammals, pigmentation patterns such as zebra stripes or tiger stripes are well-known examples of periodic patterns; more recently, the myenteric plexus (MP) of the enteric nervous system (ENS), which controls gastrointestinal motility, has been found to exhibit a striped organization in humans and laboratory mice. In domestic cats and other felids, the Transmembrane aminopeptidase Q (Taqpep) gene plays a key role in color pattern establishment during skin development, but its patterning role has not been examined in other tissues. Here, we show that, in laboratory mice, Taqpep is required for normal patterning of developing hair follicles and the MP. Using both sequencing and histologic techniques, we found Taqpep is expressed in mesenchymal cells in embryonic skin and intestine directly adjacent to where periodic patterning occurs. We generated Taqpep mutant mice, which exhibit disrupted epidermal patterning akin to the changes in periodic coat patterning observed in Taqpep mutant cats. The intestine of Taqpep mutants has irregularly periodicity of enteric neuronal stripes, and enteric neurons in Taqpep mutants exhibit disrupted Wnt signaling. This work provides new insight into the mechanism of enteric neuronal patterning and identify Taqpep as a common and conserved mediator of periodic patterning across mammalian tissues and organisms. Author summaryPeriodic patterning is a frequent motif in biology. Examples include pigmentation patterning such as tiger stripes and, as recently identified in both mouse and human, the striped organization of enteric neurons in the myenteric plexus of the intestine. In domestic and wild cats, the Transmembrane aminopeptidase Q (Taqpep) gene is essential for the establishment of periodic patterning. Whether this gene plays a conserved role in periodic patterning across other tissues and species has yet to be explored. We found that Taqpep is expressed in mesenchymal cells in embryonic mouse skin and intestine at key locations and developmental stages to instruct periodic patterning. We next generated Taqpep mutant mice that exhibit disrupted periodic patterns in both developing skin follicles and in enteric neuron organization. Thus, Taqpep is essential in establishing periodic patterning in diverse mammals and tissues.

developmental biology↗

bioRxiv2024

Molecular and genetic characterization of sex-linked orange coat color in the domestic cat

The Sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X-inactivation in female tortoiseshell and calico cats. Unlike the situation for most coat color genes, there is no apparent homolog for Sex-linked orange in other mammals. We show that the Sex-linked orange is caused by a 5 kb deletion that leads to ectopic and melanocyte-specific expression of the Rho GTPase Activating Protein 36 (Arhgap36) gene. Single cell RNA-seq studies from fetal cat skin reveal that red/yellow hair color is caused by reduced expression of melanogenic genes that are normally activated by the Melanocortin 1 receptor (Mc1r)--cyclic adenosine monophosphate (cAMP)--protein kinase A (PKA) pathway, but the Mc1r gene and its ability to stimulate cAMP accumulation is intact. Instead, we show that increased expression of Arhgap36 in melanocytes leads to reduced levels of the PKA catalytic subunit (PKAC); thus, Sex-linked orange is genetically and biochemically downstream of Mc1r. Our findings solve a comparative genomic conundrum, provide in vivo evidence for the ability of Arhgap36 to inhibit PKA, and reveal a molecular explanation for a charismatic color pattern with a rich genetic history.

genetics↗

bioRxiv2023

Unraveling the Genomic Diversity and Evolutionary History of Captive Tigers in the United States

Genomic studies of rare and endangered species have focused broadly on describing diversity patterns and resolving phylogenetic relationships, with the overarching goal of informing conservation efforts. However, few studies have investigated the genomic diversity potentially housed in captive populations. For tigers (Panthera tigris) in particular, captive individuals vastly outnumber those in the wild, yet the diversity of the captive population remains largely unexplored. Here, we present the first large-scale genetic study of the private (non-zoo) captive tiger population in the United States (U.S.), also known as Generic tigers. We find that the U.S. Generic tiger population has an admixture fingerprint comprising all six extant wild tiger subspecies (P. t. altaica, Amur; P. t. tigris, Bengal; P. t. corbetti, Indochinese; P. t. jacksoni, Malayan; P. t. amoyensis, South China; P. t. sumatrae, Sumatran). We show that the Generic tiger population has a comparable amount of genetic diversity to most wild subspecies, relatively few private variants, and fewer deleterious mutations. We also observe inbreeding coefficients that are similar to wild populations, suggesting that inbreeding in captive populations is not pervasive, although there are some individuals within the Generic population that are substantially inbred. Our results elucidate the admixture history of the Generic tiger population in the U.S. Additionally, we develop a reference panel for tigers and show that it can be used with imputation to accurately distinguish individuals and assign ancestry even with ultra-low coverage (0.25x) data. The study and reference panel will provide a resource to assist in tiger conservation efforts.

evolutionary biology↗

bioRxiv2022

Ancestry dynamics and trait selection in a designer cat breed

The Bengal cat breed was developed from intercrosses between the Asian leopard cat, Prionailurus bengalensis, and the domestic cat, Felis silvestris catus, with a last common ancestor 6 million years ago. Predicted to contain ~95% of their genome from domestic cats, regions of the leopard cat genome are thought to account for unique pelage traits and ornate color patterns of the Bengal breed, which are similar to those of ocelots and jaguars. We explore ancestry distribution and selection signatures in the Bengal breed using reduced representation and whole genome sequencing from 905 cats. Overall, leopard cat introgressions are reduced twofold from expectation and include examples of genetic incompatibility--reduced expression of a leopard cat gene in a domestic cat background--underlying the color traits Charcoal and contributing to coat color variation. Leopard cat introgressions do not show strong signatures of selection; instead, selective sweeps in Bengal cats are associated with domestic, rather than leopard cat haplotypes, and harbor candidate genes for pelage and color pattern. We identify the molecular and phenotypic basis of one selective sweep as reduced expression of the Fgfr2 gene, which underlies Glitter, a desirable trait that affects hair texture and light reflectivity.

genetics↗

bioRxiv2020

Identifying rare, medically-relevant genetic variation in a diverse population: opportunities and pitfalls

PurposeTo evaluate the effectiveness and specificity of population-based genomic screening in Alabama. MethodsThe Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5,369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. ResultsAmong 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Importantly, African-Americans were significantly enriched for FP variants, likely due to a higher rate of non-targeted alternative alleles close to array-targeted P/LP variants. ConclusionIn AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.

genetics↗

bioRxiv2018

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies, but the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins, and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p=4.93 x 10-11) than expected from the estimated mutation rate. Further, all de novo variants described here affect conserved residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. We directly assayed GTP hydrolysis and RALA effector-protein binding, and all but one tested variant significantly reduced both activities. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.\n\nAuthor SummaryWhile many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors and researchers, we have identified a set of individuals with developmental problems who all have changes to the same gene, RALA. The affected individuals all have similar symptoms, including intellectual disability, speech delay (or no speech), and problems with motor skills like walking. In nearly all of these cases (10 of 11), the genetic change found in the child was not inherited from either parent. The locations and biological properties of these changes suggest that they are likely to disrupt the normal functions of RALA and cause significant health problems. We also performed experiments to show that the genetic changes found in these individuals alter two key functions of RALA. Together, we have provided evidence that genetic changes in RALA can cause DD/ID. These results will allow doctors and researchers to identify additional children with the same condition, providing a clinical diagnosis to these families and leading to new research opportunities.

genetics↗

bioRxiv2017

Genomic sequencing identifies secondary findings in a cohort of parent study participants

PURPOSEClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.\n\nMETHODSExome/genome sequencing and analysis of 789 unaffected parents was performed.\n\nRESULTSPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the ACMG. Of the 25 individuals, five carried a variant consistent with a previous clinical diagnosis, thirteen were not previously diagnosed but had symptoms or family history with probable association with the detected variant, and seven reported no symptoms or family history of disease. A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate-pairs to identify cases in which both parents were carriers for the same recessive disease; this led to one finding in ATP7B. Four participants had two findings (one carrier and one non-carrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.\n\nCONCLUSIONWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design, and implementation of research and clinical sequencing efforts to identify such findings.

genomics↗

bioRxiv2016

Genomic diagnosis for children with intellectual disability and/or developmental delay

BackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.\n\nMethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).\n\nResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.\n\nConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

genomics↗