Morphological Variation, Karyology, and Systematic Relationships of \u3ci\u3eHeteromys gaumeri\u3c/i\u3e (Rodentia: Heteromyidae)

Morphological variation was assessed within and among populations of Heteromys gaumeri using univariate and multivariate statistical analyses of external and cranial measurements. Although patterns and amount of nongeographic variation in H. gaumeri were similar to other heteromyines, geographic variation was relatively conservative. Mean values of most characters were statistically homogeneous among localities and spatially unpatterned. Consequently, no association was found between levels of within- and among-sample variation for individual characters (the Kluge-Kerfoot phenomenon ). Populations of H. gaumeri were chromosomally monomorphic. The lack of morphological and chromosomal variation in H. gaumeri contrasts sharply with patterns in other heteromyines. Heteromys gaumeri is morphologically and chromosomally distinct from the H. desmarestianus species group (to which it is currently assigned) and appears to share some primitive characters with Liomys (the sister group of Heteromys). We recommend that H. gaumeri be removed from the H. desmarestianus group. Spanish abstract: La variación morfológica intra e interpoblacional de Heteromys gaumeri fue evaluada usando análisis estadísticos univariados y multivariados de medidas externas y craneales. A pesar de que los patrones y cantidad de variación intrapoblacional en H. gaumeri fue similar a la de otros heterominos, la variación geográfica fue relativamente conservadora. Los valores promedio de la mayoría de los caracteres fueron estadisticamente homogeneos entre las localidades, sin mostrar ningún patrón de variación espacial. En conservencia, no se encontró asociación alguna entre los niveles de variación intra e interpoblacional para caracteres individuates ( fenómena Kluge-Kerfoot ), Las poblaciones de H. gaumeri fueron monomórficas cromosómicamente. La falta de variacion tanto morfológica como cronosómica en H. gaumeri contrasta marcadamente con los patrones encontrados anteriormente para otros heteróminos. Heteromys gaumeri es morfológica y cromosómicamente distinguible del grupo H. desmarestianus (al cual se asigna actualmente) y aparentemente comparte algunos caracteres primitives con Liomys (el grupo hermano de Heteromys). Nosotros recomendamos que se remueva a H. gaumeri del grupo H. desmarestianus. Portuguese abstract: Avalia-se a variação morfológica intra- e interpopulacional de Heteromys gaumeri, através de análises estatisticas uni- e multivariadas de medidas externas e craniais. Apesar dos padrões, e da quantidade de variação intrapopulacional em H. gaumeri serem similares aos de outros heteromídeos, a variação geográfica é relativamente conservadora. Os valores médios da maior parte dos caráteres examinados são estatìsticamente homogeneos entre as localidades, e não surgiu nenhum padrão de variações locais. Consequentemente, não foram encontradas assoçiacões entre os níveis de varaiações intra- e interpopulacionais para caráteres individuais (o “fenômeno Kluge-Kerfoot”). Populações de H. gaumeri mostraram-se cromossômicamente monomórficas. A falta de variação morfológica ou cromossômica em H. gaumeri é altamente contrastante aos padrões encontrados em outros heteromídeos. Heteromys gaumeri distinguese tanto morfológica quanto cromossômicamente do grupo H. desmarestianus, ao qual está atualmente designado, e aparentemente possue caráteres primitivos em comum com Liomys—grupo irmão de Heteromys. Recomendamos que H. gaumeri seja removido do grupo H. desmarestianus

Morphological Variation, Karyology, and Systematic Relationships of \u3ci\u3eHeteromys gaumeri\u3c/i\u3e (Rodentia: Heteromyidae)

Morphological variation was assessed within and among populations of Heteromys gaumeri using univariate and multivariate statistical analyses of external and cranial measurements. Although patterns and amount of nongeographic variation in H. gaumeri were similar to other heteromyines, geographic variation was relatively conservative. Mean values of most characters were statistically homogeneous among localities and spatially unpatterned. Consequently, no association was found between levels of within- and among-sample variation for individual characters (the Kluge-Kerfoot phenomenon ). Populations of H. gaumeri were chromosomally monomorphic. The lack of morphological and chromosomal variation in H. gaumeri contrasts sharply with patterns in other heteromyines. Heteromys gaumeri is morphologically and chromosomally distinct from the H. desmarestianus species group (to which it is currently assigned) and appears to share some primitive characters with Liomys (the sister group of Heteromys). We recommend that H. gaumeri be removed from the H. desmarestianus group. Spanish abstract: La variación morfológica intra e interpoblacional de Heteromys gaumeri fue evaluada usando análisis estadísticos univariados y multivariados de medidas externas y craneales. A pesar de que los patrones y cantidad de variación intrapoblacional en H. gaumeri fue similar a la de otros heterominos, la variación geográfica fue relativamente conservadora. Los valores promedio de la mayoría de los caracteres fueron estadisticamente homogeneos entre las localidades, sin mostrar ningún patrón de variación espacial. En conservencia, no se encontró asociación alguna entre los niveles de variación intra e interpoblacional para caracteres individuates ( fenómena Kluge-Kerfoot ), Las poblaciones de H. gaumeri fueron monomórficas cromosómicamente. La falta de variacion tanto morfológica como cronosómica en H. gaumeri contrasta marcadamente con los patrones encontrados anteriormente para otros heteróminos. Heteromys gaumeri es morfológica y cromosómicamente distinguible del grupo H. desmarestianus (al cual se asigna actualmente) y aparentemente comparte algunos caracteres primitives con Liomys (el grupo hermano de Heteromys). Nosotros recomendamos que se remueva a H. gaumeri del grupo H. desmarestianus. Portuguese abstract: Avalia-se a variação morfológica intra- e interpopulacional de Heteromys gaumeri, através de análises estatisticas uni- e multivariadas de medidas externas e craniais. Apesar dos padrões, e da quantidade de variação intrapopulacional em H. gaumeri serem similares aos de outros heteromídeos, a variação geográfica é relativamente conservadora. Os valores médios da maior parte dos caráteres examinados são estatìsticamente homogeneos entre as localidades, e não surgiu nenhum padrão de variações locais. Consequentemente, não foram encontradas assoçiacões entre os níveis de varaiações intra- e interpopulacionais para caráteres individuais (o “fenômeno Kluge-Kerfoot”). Populações de H. gaumeri mostraram-se cromossômicamente monomórficas. A falta de variação morfológica ou cromossômica em H. gaumeri é altamente contrastante aos padrões encontrados em outros heteromídeos. Heteromys gaumeri distinguese tanto morfológica quanto cromossômicamente do grupo H. desmarestianus, ao qual está atualmente designado, e aparentemente possue caráteres primitivos em comum com Liomys—grupo irmão de Heteromys. Recomendamos que H. gaumeri seja removido do grupo H. desmarestianus

Natural History and Karyology of the Yucatán Vesper Mouse, \u3ci\u3eOtonyctomys hatti\u3c/i\u3e

Seventeen specimens of the rare Yucatán vesper mouse, Otonyctomys hatti, are now known from Belize, Guatemala, and the Mexican states of Campeche, Quintana Roo, and Yucatán. We herein report a second specimen of O. hatti, from Belize, extending the known geographic range of the species 95 km to the southeast in the country. This is the first location at which O. hatti has been taken sympatrically with the Central American vesper mouse, Nyctomys sumichrasti. We also report data on three additional specimens of O. hatti from Campeche. Nyctomys and Otonyctomys share similar habits and habitat requirements, and might compete where they overlap. However, the distribution of O. hatti corresponds closely to that of other Yucatán endemic, and the distinct distributions of the two genera probably reflects biogeographic history and different habitat requirements, rather than result from direct competition. The karyotype of O. hatti is 2n=50, F=58. Although superficially similar, it differs in important respects with the karyotypes reported for N. sumichrasti

Natural History and Karyology of the Yucatán Vesper Mouse, \u3ci\u3eOtonyctomys hatti\u3c/i\u3e

Seventeen specimens of the rare Yucatán vesper mouse, Otonyctomys hatti, are now known from Belize, Guatemala, and the Mexican states of Campeche, Quintana Roo, and Yucatán. We herein report a second specimen of O. hatti, from Belize, extending the known geographic range of the species 95 km to the southeast in the country. This is the first location at which O. hatti has been taken sympatrically with the Central American vesper mouse, Nyctomys sumichrasti. We also report data on three additional specimens of O. hatti from Campeche. Nyctomys and Otonyctomys share similar habits and habitat requirements, and might compete where they overlap. However, the distribution of O. hatti corresponds closely to that of other Yucatán endemic, and the distinct distributions of the two genera probably reflects biogeographic history and different habitat requirements, rather than result from direct competition. The karyotype of O. hatti is 2n=50, F=58. Although superficially similar, it differs in important respects with the karyotypes reported for N. sumichrasti

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide

The Reality of Pervasive Transcription

Despite recent controversies, the evidence that the majority of the human genome is transcribed into RNA remains strong