Livestock species as emerging models for genomic imprinting.

Genomic imprinting is an epigenetically-regulated process of central importance in mammalian development and evolution. It involves multiple levels of regulation, with spatio-temporal heterogeneity, leading to the context-dependent and parent-of-origin specific expression of a small fraction of the genome. Genomic imprinting studies have therefore been essential to increase basic knowledge in functional genomics, evolution biology and developmental biology, as well as with regard to potential clinical and agrigenomic perspectives. Here we offer an overview on the contribution of livestock research, which features attractive resources in several respects, for better understanding genomic imprinting and its functional impacts. Given the related broad implications and complexity, we promote the use of such resources for studying genomic imprinting in a holistic and integrative view. We hope this mini-review will draw attention to the relevance of livestock genomic imprinting studies and stimulate research in this area.

Detection of DNA methylation signatures through the lens of genomic imprinting.

Genomic imprinting represents an original model of epigenetic regulation resulting in a parent-of-origin expression. Despite the critical role of imprinted genes in mammalian growth, metabolism and neuronal function, there is no molecular tool specifically targeting them for a systematic evaluation. We show here that enzymatic methyl-seq consistently outperforms the bisulfite-based standard in capturing 165 candidate regions for genomic imprinting in the pig. This highlights the potential for a turnkey, fully customizable and reliable capture tool of genomic regions regulated by cytosine methylation in any population of interest. For the field of genomic imprinting, it opens up the possibility of detecting multilocus imprinting variations across the genome, with implications for basic research, agrigenomics and clinical practice.

Genomic Imprinting in the New Omics Era: A Model for Systems-Level Approaches.

Genomic imprinting represents a noteworthy inheritance mechanism leading to allele-specific regulations dependent of the parental origin. Imprinted loci are especially involved in essential mammalian functions related to growth, development and behavior. In this mini-review, we first offer a summary of current representations associated with genomic imprinting through key results of the three last decades. We then outline new perspectives allowed by the spread of new omics technologies tackling various interacting levels of imprinting regulations, including genomics, transcriptomics and epigenomics. We finally discuss the expected contribution of new omics data to unresolved big questions in the field.

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma.

Background: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. Results: We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.

Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma.

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained 2-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii).

Devil Facial Tumor Disease (DFTD) is an aggressive cancer notorious for its rare etiology and its impact on Tasmanian devil populations. Two regions underlying an evolutionary response to this cancer were recently identified using genomic time-series pre- and post-DTFD arrival. Here, we support that DFTD shaped the genome of the Tasmanian devil in an even more extensive way than previously reported. We detected 97 signatures of selection, including 148 protein coding genes having a human orthologue, linked to DFTD. Most candidate genes are associated with cancer progression, and an important subset of candidate genes has additional influence on social behavior. This confirms the influence of cancer on the ecology and evolution of the Tasmanian devil. Our work also demonstrates the possibility to detect highly polygenic footprints of short-term selection in very small populations.

How could fully scaled carps appear in natural waters in Madagascar?

The capacity of organisms to rapidly evolve in response to environmental changes is a key feature of evolution, and studying mutation compensation is a way to evaluate whether alternative routes of evolution are possible or not. Common carps (Cyprinus carpio) carrying a homozygous loss-of-function mutation for the scale cover gene fgfr1a1, causing the 'mirror' reduced scale cover, were introduced in Madagascar a century ago. Here we show that carps in Malagasy natural waters are now predominantly covered with scales, though they still all carry the homozygous mutation. We also reveal that the number of scales in mutated carps is under strong polygenic genetic control, with a heritability of 0.49. As a whole, our results suggest that carps submitted to natural selection could evolve a wild-type-like scale cover in less than 40 generations from standing polygenic genetic variation, confirming similar findings mainly retrieved from model organisms.