Vitamin D Pathway Gene Variants and Prostate Cancer Risk

Vitamin D has antiproliferative, antiangiogenic, and apoptotic properties. There is some evidence supporting an association between vitamin D-related gene variants and prostate cancer risk. We report results from this population-based case-control study of genes encoding for the vitamin D receptor (VDR), the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1). Forty-eight tagging single nucleotide polymorphisms (tagSNP) were analyzed in 827 incident prostate cancer cases diagnosed from 2002 to 2005, and in 787 age-matched controls. Contrary to some earlier studies, we found no strong evidence of altered risk of developing prostate cancer overall or within clinical measures of tumor aggressiveness for any of the tagSNPs when they were assessed individually or in haplotypes

The genetic hallmarks of dog breed development reveal shared patterns of historical human-dog interactions

Each Approximately 15,000 years ago, the wild grey wolf gave rise to the first domestic dogs. Multiple domestication events likely took place throughout modern day Eurasia, though the precise times and locations are a hotly debated topic among researchers. Distinct populations of dogs, varying in physical appearance and behavior, developed to reflect the needs or desires of the human cultures in which they were formed. Rich in history, Italy is home to at least 24 unique dog breeds. Genetic analysis of these breeds, in relation to global dog breeds, has highlighted key technological advancements and movements of the region\u2019s people. We have analyzed DNA from 1,609 dogs, representing 182 breeds, and 16 wild canids, on a panel of 142,840 markers genomewide. Twenty-four of these breeds are native to Italy, with 3 represented by both Italian and American populations. Through analysis of phylogeny and identity-by-descent haplotype sharing, patterns of breed formation have emerged that parallel the developmental progression of humans. Selection for common physical and behavioral phenotypes in hunting sighthounds, without evidence of recent shared genetic history, reveals shared human needs and biologically ideal forms. Identification of breed relationships to the isolated Fonni\u2019s Dog of Sardinia exposes geographic regions of development and tracks shared migration with human cultures. Finally, molecular evidence of historic agricultural practices is observed in the shared genetics of livestock guardian breeds

Studies of modern Italian dog populations reveal multiple patterns for domestic breed evolution

Through thousands of years of breeding and strong human selection, the dog (Canis lupus familiaris) exists today within hundreds of closed populations throughout the world, each with defined phenotypes. A singular geographic region with broad diversity in dog breeds presents an interesting opportunity to observe potential mechanisms of breed formation. Italy claims 14 internationally recognized dog breeds, with numerous additional local varieties. To determine the relationship among Italian dog populations, we integrated genetic data from 263 dogs representing 23 closed dog populations from Italy, seven Apennine gray wolves, and an established dataset of 161 globally recognized dog breeds, applying multiple genetic methods to characterize the modes by which breeds are formed within a single geographic region. Our consideration of each of five genetic analyses reveals a series of development events that mirror historical modes of breed formation, but with variations unique to the codevelopment of early dog and human populations. Using 142,840 genome-wide SNPs and a dataset of 1,609 canines, representing 182 breeds and 16 wild canids, we identified breed development routes for the Italian breeds that included divergence from common populations for a specific purpose, admixture of regional stock with that from other regions, and isolated selection of local stock with specific attributes

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry–specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13–7.22) and 33.41 (95% CI = 10.86–102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17–25%) for TA heterozygotes and 38% (95% CI = 13–65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. Patient summary: We found that rs72725854, an African ancestry–specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening. © 2020 The AuthorsThe African ancestry–specific prostate cancer risk variant at 8q24, rs72725854, is enriched in men diagnosed at younger ages and men with a prostate cancer family history. Carriers of this risk allele would benefit from regular and earlier prostate cancer screening

Universal DNA methylation age across mammalian tissues

DATA AVAILABILITY STATEMENT : The individual-level data from the Mammalian Methylation Consortium can be accessed from several online locations. All data from the Mammalian Methylation Consortium are posted on Gene Expression Omnibus (complete dataset, GSE223748). Subsets of the datasets can also be downloaded from accession numbers GSE174758, GSE184211, GSE184213, GSE184215, GSE184216, GSE184218, GSE184220, GSE184221, GSE184224, GSE190660, GSE190661, GSE190662, GSE190663, GSE190664, GSE174544, GSE190665, GSE174767, GSE184222, GSE184223, GSE174777, GSE174778, GSE173330, GSE164127, GSE147002, GSE147003, GSE147004, GSE223943 and GSE223944. Additional details can be found in Supplementary Note 2. The mammalian data can also be downloaded from the Clock Foundation webpage: https://clockfoundation.org/MammalianMethylationConsortium. The mammalian methylation array is available through the non-profit Epigenetic Clock Development Foundation (https://clockfoundation.org/). The manifest file of the mammalian array and genome annotations of CpG sites can be found on Zenodo (10.5281/zenodo.7574747). All other data supporting the findings of this study are available from the corresponding author upon reasonable request. The chip manifest files, genome annotations of CpG sites and the software code for universal pan-mammalian clocks can be found on GitHub95 at https://github.com/shorvath/MammalianMethylationConsortium/tree/v2.0.0. The individual R code for the universal pan-mammalian clocks, EWAS analysis and functional enrichment studies can be also found in the Supplementary Code.SUPPLEMENTARY MATERIAL 1 : Supplementary Tables 1–3 and Notes 1–6.SUPPLEMENTARY MATERIAL 2 : Reporting SummarySUPPLEMENTARY MATERIAL 3 : Supplementary Data 1–14.SUPPLEMENTARY MATERIAL 4 : Supplementary Code.Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.https://www.nature.com/nataginghj2024Zoology and EntomologySDG-15:Life on lan

Commonalities in development of pure breeds and population isolates revealed in the genome of the Sardinian Fonni&#8217;s dog

The island inhabitants of Sardinia have long been a focus for studies of complex human traits due to their unique ancestral background and population isolation reflecting geographic and cultural restriction. Population isolates share decreased genomic diversity, increased linkage disequilibrium, and increased inbreeding coefficients. In many regions, dogs and humans have been exposed to the same natural and artificial forces of environment, growth, and migration. Distinct dog breeds have arisen through human-driven selection of characteristics to meet an ideal standard of appearance and function. The Fonni's Dog, an endemic dog population on Sardinia, has not been subjected to an intensive system of artificial selection, but rather has developed alongside the human population of Sardinia, influenced by geographic isolation and unregulated selection based on its environmental adaptation and aptitude for owner-desired behaviors. Through analysis of 28 dog breeds, represented with whole-genome sequences from 13 dogs and ~170K genome-wide single nucleotide variants from 155 dogs, we have produced a genomic illustration of the Fonni's Dog. Genomic patterns confirm within-breed similarity, while population and demographic analyses provide spatial identity of Fonni's Dog to other Mediterranean breeds. Investigation of admixture and fixation indices reveal insights into the Fonni's Dog's involvement in breed development throughout the Mediterranean. We describe how characteristics of population isolates are reflected in dog breeds that have undergone artificial selection, and are mirrored in the Fonni's Dog through traditional isolating factors that affect human populations. Lastly, we show that the genetic history of Fonni's Dog parallels demographic events in local human populations

Whole genome analysis of the Lupo Italiano

The Lupo Italiano (Italian Wolfdog) is a domestic dog (Canis lupus familiaris) breed created in 1966 by crossing of Apennine grey wolves (Canis lupus italicus) to German Shepherd dogs (GSD). The breed has an official studbook with management protocols, under the control of the Ministry of Agriculture. The breed is characterized by strength, resistance, and strong capabilities in learning, as well as participation in search and rescue activities. Considering the depth and completeness of genealogical information, the high levels of inbreeding, and the presence of the wolf as a recent ancestor, the Lupo Italiano can be used as a model to investigate the effects of population structure and selection on wolf-dog hybridization. The aim of this work is to compare the genetic background of the Italian Wolfdog with that of the GSD, village dogs, grey wolves from the Apennines, and other dog populations, with a specific goal of detailing introgression between the Lupo Italiano, wolf and GSD. Three hundred and seventy-seven individuals were genotyped using a high density chip containing more than 170K SNPs. Genotypes for Lupo Italiano were provided by University of Milano and National Institutes of Health in Bethesda, MD. Those for the Apennine wolves were produced by ISPRA, and those for GSD, village dogs and grey wolves were publicly available (Dryad, Shannon et al. 2015). Samples and loci were quality checked, and then analyzed using Multi-Dimensional Scaling (MDS). The relationship matrix based on pedigrees was compared with the genomic relationship matrix (GRM), calculated using GCTA64 software. In addition, the genomic heterozygosity-based inbreeding coefficient has been estimated using PLINK v1.9 software. Reynolds distances were computed to define the relationships among the five populations. In addition, the Lupo Italiano, wolves and GSD were studied at the chromosomal level. As expected, the closest population to the Lupo Italiano is the German Shepherd dog (Reynold genetic distance 0.25), whereas the farthest is the Apennine Wolf (0.40). Results are expected to provide a clear picture of the genomic structure of the Lupo Italiano and its hybridization history. Beside scientific interest, these findings will allow the breeder association (AAALI) to better manage their animals and conserve breed genetic variation

Dog10K : An international sequencing effort to advance studies of canine domestication, phenotypes and health

Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health. © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.Peer reviewe