Genetic risk prediction in Hispanics/Latinos: milestones, challenges, and social-ethical considerations.

Genome-wide association studies (GWAS) have allowed the identification of disease-associated variants, which can be leveraged to build polygenic scores (PGSs). Even though PGSs can be a valuable tool in personalized medicine, their predictive power is limited in populations of non-European ancestry, particularly in admixed populations. Recent efforts have focused on increasing racial and ethnic diversity in GWAS, thus, addressing some of the limitations of genetic risk prediction in these populations. Even with these efforts, few studies focus exclusively on Hispanics/Latinos. Additionally, Hispanic/Latino populations are often considered a single population despite varying admixture proportions between and within ethnic groups, diverse genetic heterogeneity, and demographic history. Combined with highly heterogeneous environmental and socioeconomic exposures, this diversity can reduce the transferability of genetic risk prediction models. Given the recent increase of genomic studies that include Hispanics/Latinos, we review the milestones and efforts that focus on genetic risk prediction, summarize the potential for improving PGS transferability, and highlight the challenges yet to be addressed. Additionally, we summarize social-ethical considerations and provide ideas to promote genetic risk prediction models that can be implemented equitably.

An Atypical 15q11.2 Microdeletion Not Involving SNORD116 Resulting in Prader-Willi Syndrome.

Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the SNURF-SNRPN promoter, including the SNORD116 snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of SNURF-SNRPN with apparently preserved expression of SNORD116.

Congenital diaphragmatic hernia in siblings with PIGA-related congenital disorder of glycosylation.

There are over 150 proteins involved in glycosylphosphatidylinositol (GPI)-anchored protein biosynthesis, a class within the larger category of congenital disorders of glycosylation (CDG). Pathogenic variants identified in phosphatidylinositol glycan class A protein (PIGA) are associated with X-linked PIGA-CDG, a GPI-anchor defect. The disease has primarily been characterized by hypotonia, epilepsy, and global developmental delay; however, only 89 known cases are reported, so the phenotypic spectrum has likely not yet been fully delineated. Congenital diaphragmatic hernia (CDH) has been reported in patients with various GPI-anchor related defects but has only been described in one prior individual with PIGA-CDG. Here, we describe the second and third reported cases of CDH in two brothers with PIGA-CDG caused by a pathogenic missense variant in PIGA: c.355C > T, p.R119W. Chromosomal microarray and whole exome sequencing did not reveal another plausible explanation for the CDH. We relate our patients' clinical features to the single previously reported individual with CDH and PIGA-CDG. We then compare this case series with the subset of individuals with CDH and other GPI-anchor defects. These findings suggest that CDH should be considered in the phenotypic disease spectrum of PIGA-CDG.

Identification of a novel subgroup of endometrial cancer patients with loss of thyroid hormone receptor beta expression and improved survival.

BACKGROUND: Endometrial cancer (EC) is the most common gynecologic cancer in women, and the incidence of EC has increased by about 1% per year in the U. S over the last 10 years. Although 5-year survival rates for early-stage EC are around 80%, certain subtypes of EC that lose nuclear hormone receptor (NHR) expression are associated with poor survival rates. For example, estrogen receptor (ER)-negative EC typically harbors a worse prognosis compared to ER-positive EC. The molecular basis for the loss of NHR expression in endometrial tumors and its contribution to poor survival is largely unknown. Furthermore, there are no tools to systematically identify tumors that lose NHR mRNA expression relative to normal tissue. The development of such an approach could identify sets of NHR-based biomarkers for classifying patients into subgroups with poor survival outcomes. METHODS: Here, a new computational method, termed receptLoss, was developed for identifying NHR expression loss in endometrial cancer relative to adjacent normal tissue. When applied to gene expression data from The Cancer Genome Atlas (TCGA), receptLoss identified 6 NHRs that were highly expressed in normal tissue and exhibited expression loss in a subset of endometrial tumors. RESULTS: Three of the six identified NHRs - estrogen, progesterone, and androgen receptors - that are known to lose expression in ECs were correctly identified by receptLoss. Additionally, a novel association was found between thyroid hormone receptor beta (THRB) expression loss, increased expression of miRNA-146a, and increased rates of 5-year survival in the EC TCGA patient cohort. THRB expression loss occurs independently of estrogen and progesterone expression loss, suggesting the discovery of a distinct, clinically-relevant molecular subgroup. CONCLUSION: ReceptLoss is a novel, open-source software tool to systematically identify NHR expression loss in cancer. The application of receptLoss to endometrial cancer gene expression data identified THRB, a previously undescribed biomarker of survival in endometrial cancer. Applying receptLoss to expression data from additional cancer types could lead to the development of biomarkers of disease progression for patients with any other tumor type. ReceptLoss can be applied to expression data from additional cancer types with the goal of identifying biomarkers of differential survival.

Aneuvis: web-based exploration of numerical chromosomal variation in single cells.

BACKGROUND: Numerical chromosomal variation is a hallmark of populations of malignant cells. Identifying the factors that promote numerical chromosomal variation is important for understanding mechanisms of carcinogenesis. However, the ability to quantify and visualize differences in chromosome number between experimentally-defined groups (e.g. control vs treated) obtained from single-cell experiments is currently limited by the lack of user-friendly software. RESULTS: Aneuvis is a web application that allows users to determine whether numerical chromosomal variation exists between experimental treatment groups. The web interface allows users to upload molecular cytogenetic or processed single cell whole-genome sequencing data in a cell-by-chromosome matrix format and automatically generates visualizations and summary statistics that reflect the degree of numeric chromosomal variability. CONCLUSIONS: Aneuvis is the first user-friendly web application to help researchers identify the genetic and environmental perturbations that promote numerical chromosomal variation. Aneuvis is freely available as a web application at https://dpique.shinyapps.io/aneuvis/ and the source code for the application is available at https://github.com/dpique/aneuvis .

A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma.

BACKGROUND: Oncogenes promote the development of therapeutic targets against subsets of cancers. Only several hundred oncogenes have been identified, primarily via mutation-based approaches, in the human genome. Transcriptional overexpression is a less-explored mechanism through which oncogenes can arise. METHODS: Here, a new statistical approach, termed oncomix, which captures transcriptional heterogeneity in tumour and adjacent normal (i.e., tumour-free) mRNA expression profiles, was developed to identify oncogene candidates that were overexpressed in a subset of breast tumours. RESULTS: Intronic DNA methylation was strongly associated with the overexpression of chromobox 2 (CBX2), an oncogene candidate that was identified using our method but not through prior analytical approaches. CBX2 overexpression in breast tumours was associated with the upregulation of genes involved in cell cycle progression and with poorer 5-year survival. The predicted function of CBX2 was confirmed in vitro, providing the first experimental evidence that CBX2 promotes breast cancer cell growth. CONCLUSIONS: Oncomix is a novel approach that captures transcriptional heterogeneity between tumour and adjacent normal tissue, and that has the potential to uncover therapeutic targets that benefit subsets of cancer patients. CBX2 is an oncogene candidate that should be further explored as a potential drug target for aggressive types of breast cancer.

Role for Mycobacterium tuberculosis membrane vesicles in iron acquisition.

Mycobacterium tuberculosis releases membrane vesicles packed with molecules that can modulate the immune response. Because environmental conditions often influence the production and content of bacterial vesicles, this study examined M. tuberculosis microvesicles released under iron limitation, a common condition faced by pathogens inside the host. The findings indicate that M. tuberculosis increases microvesicle production in response to iron restriction and that these microvesicles contain mycobactin, which can serve as an iron donor and supports replication of iron-starved mycobacteria. Consequently, the results revealed a role of microvesicles in iron acquisition in M. tuberculosis, which can be critical for survival in the host.

Molecular evolution of a Y chromosome to autosome gene duplication in Drosophila.

In contrast to the rest of the genome, the Y chromosome is restricted to males and lacks recombination. As a result, Y chromosomes are unable to respond efficiently to selection, and newly formed Y chromosomes degenerate until few genes remain. The rapid loss of genes from newly formed Y chromosomes has been well studied, but gene loss from highly degenerate Y chromosomes has only recently received attention. Here, we identify and characterize a Y to autosome duplication of the male fertility gene kl-5 that occurred during the evolution of the testacea group species of Drosophila. The duplication was likely DNA based, as other Y-linked genes remain on the Y chromosome, the locations of introns are conserved, and expression analyses suggest that regulatory elements remain linked. Genetic mapping reveals that the autosomal copy of kl-5 resides on the dot chromosome, a tiny autosome with strongly suppressed recombination. Molecular evolutionary analyses show that autosomal copies of kl-5 have reduced polymorphism and little recombination. Importantly, the rate of protein evolution of kl-5 has increased significantly in lineages where it is on the dot versus Y linked. Further analyses suggest this pattern is a consequence of relaxed purifying selection, rather than adaptive evolution. Thus, although the initial fixation of the kl-5 duplication may have been advantageous, slightly deleterious mutations have accumulated in the dot-linked copies of kl-5 faster than in the Y-linked copies. Because the dot chromosome contains seven times more genes than the Y and is exposed to selection in both males and females, these results suggest that the dot suffers the deleterious effects of genetic linkage to more selective targets compared with the Y chromosome. Thus, a highly degenerate Y chromosome may not be the worst environment in the genome, as is generally thought, but may in fact be protected from the accumulation of deleterious mutations relative to other nonrecombining regions that contain more genes.