Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia.

Objectives: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients.

Methods: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors.

Sex differences in early and term placenta are conserved in adult tissues.

Background: Pregnancy complications vary based on the fetus's genetic sex, which may, in part, be modulated by the placenta. Furthermore, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different timepoints throughout pregnancy and comparisons to adult tissues remains poorly characterized.

Erratum: X chromosome inactivation in the human placenta is patchy and distinct from adult tissues.

[This corrects the article DOI: 10.1016/j.xhgg.

X chromosome inactivation in the human placenta is patchy and distinct from adult tissues.

In humans, one of the X chromosomes in genetic females is inactivated by a process called X chromosome inactivation (XCI). Variation in XCI across the placenta may contribute to observed sex differences and variability in pregnancy outcomes. However, XCI has predominantly been studied in human adult tissues.

Unique evolutionary trajectories of breast cancers with distinct genomic and spatial heterogeneity.

Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2 genotypes. The latter included a germ line carrier and a patient with a somatic variant.

Identification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations.

Annotations of evolutionary sequence constraint based on multi-species genome alignments and genome-wide maps of epigenomic marks and transcription factor binding provide important complementary information for understanding the human genome and genetic variation. Here we developed the Constrained Non-Exonic Predictor (CNEP) to quantify the evidence of each base in the genome being in an evolutionarily constrained non-exonic element from an input of over 60,000 epigenomic and transcription factor binding features. We find that the CNEP score outperforms baseline and related existing scores at predicting evolutionarily constrained non-exonic bases from such data.

Unique genomic and neoepitope landscapes across tumors: a study across time, tissues, and space within a single lynch syndrome patient.

Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes. LS is the most common inherited cancer predisposition condition and confers an elevated lifetime risk of multiple cancers notably colorectal and endometrial carcinomas. A distinguishing feature of LS associated tumors is accumulation of variants targeting microsatellite repeats and the potential for high tumor specific neoepitope levels.

Neoantigen Fitness Model Predicts Lower Immune Recognition of Cutaneous Squamous Cell Carcinomas Than Actinic Keratoses.

A low percentage of actinic keratoses progress to develop into cutaneous squamous cell carcinoma. The immune mechanisms that successfully control or eliminate the majority of actinic keratoses and the mechanisms of immune escape by invasive squamous cell carcinoma are not well-understood. Here, we took a systematic approach to evaluate the neoantigens present in actinic keratosis and cutaneous squamous cell carcinoma specimens.

Identifying, understanding, and correcting technical artifacts on the sex chromosomes in next-generation sequencing data.

Background: Mammalian X and Y chromosomes share a common evolutionary origin and retain regions of high sequence similarity. Similar sequence content can confound the mapping of short next-generation sequencing reads to a reference genome. It is therefore possible that the presence of both sex chromosomes in a reference genome can cause technical artifacts in genomic data and affect downstream analyses and applications.

Complex patterns of sex-biased demography in canines.

The demographic history of dogs is complex, involving multiple bottlenecks, admixture events and artificial selection. However, existing genetic studies have not explored variance in the number of reproducing males and females, and whether it has changed across evolutionary time. While male-biased mating practices, such as male-biased migration and multiple paternity, have been observed in wolves, recent breeding practices could have led to female-biased mating patterns in breed dogs.

Comparison of Single Genome and Allele Frequency Data Reveals Discordant Demographic Histories.

Inference of demographic history from genetic data is a primary goal of population genetics of model and nonmodel organisms. Whole genome-based approaches such as the pairwise/multiple sequentially Markovian coalescent methods use genomic data from one to four individuals to infer the demographic history of an entire population, while site frequency spectrum (SFS)-based methods use the distribution of allele frequencies in a sample to reconstruct the same historical events. Although both methods are extensively used in empirical studies and perform well on data simulated under simple models, there have been only limited comparisons of them in more complex and realistic settings.

Determining the Effect of Natural Selection on Linked Neutral Divergence across Species.

A major goal in evolutionary biology is to understand how natural selection has shaped patterns of genetic variation across genomes. Studies in a variety of species have shown that neutral genetic diversity (intra-species differences) has been reduced at sites linked to those under direct selection. However, the effect of linked selection on neutral sequence divergence (inter-species differences) remains ambiguous.

CASZ1 inhibits cell cycle progression in neuroblastoma by restoring pRb activity.

Dysregulation of cell cycle genes such as Cyclin D1 and Chk1 contributes to the undifferentiated phenotype of neuroblastoma (NB). CASZ1 functions as a tumor suppressor in NB; here we sought to determine how loss of CASZ1 contributes to cell cycle dysregulation in NB. CASZ1 restoration in NB cells delays NB cell cycle progression.