Clock genes and their genomic distributions in three species of salmonid fishes: Associations with genes regulating sexual maturation and cell cycling

<p>Abstract</p> <p>Background</p> <p>Clock family genes encode transcription factors that regulate clock-controlled genes and thus regulate many physiological mechanisms/processes in a circadian fashion. Clock1 duplicates and copies of Clock3 and NPAS2-like genes were partially characterized (genomic sequencing) and mapped using family-based indels/SNPs in rainbow trout (RT)(<it>Oncorhynchus mykiss</it>), Arctic charr (AC)(<it>Salvelinus alpinus</it>), and Atlantic salmon (AS)(<it>Salmo salar</it>) mapping panels.</p> <p>Results</p> <p>Clock1 duplicates mapped to linkage groups RT-8/-24, AC-16/-13 and AS-2/-18. Clock3/NPAS2-like genes mapped to RT-9/-20, AC-20/-43, and AS-5. Most of these linkage group regions containing the Clock gene duplicates were derived from the most recent 4R whole genome duplication event specific to the salmonids. These linkage groups contain quantitative trait loci (QTL) for life history and growth traits (i.e., reproduction and cell cycling). Comparative synteny analyses with other model teleost species reveal a high degree of conservation for genes in these chromosomal regions suggesting that functionally related or co-regulated genes are clustered in syntenic blocks. For example, anti-müllerian hormone (amh), regulating sexual maturation, and ornithine decarboxylase antizymes (oaz1 and oaz2), regulating cell cycling, are contained within these syntenic blocks.</p> <p>Conclusions</p> <p>Synteny analyses indicate that regions homologous to major life-history QTL regions in salmonids contain many candidate genes that are likely to influence reproduction and cell cycling. The order of these genes is highly conserved across the vertebrate species examined, and as such, these genes may make up a functional cluster of genes that are likely co-regulated. CLOCK, as a transcription factor, is found within this block and therefore has the potential to cis-regulate the processes influenced by these genes. Additionally, clock-controlled genes (CCGs) are located in other life-history QTL regions within salmonids suggesting that at least in part, trans-regulation of these QTL regions may also occur via Clock expression.</p

Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

We used human bladder cancer as a model system and the whole-organ histologic and genetic mapping strategy to identify clonal genetic hits associated with growth advantage, tracking the evolution of bladder cancer from intraurothelial precursor lesions. Six putative chromosomal regions critical for clonal expansion of intraurothelial neoplasia and development of bladder cancer were identified by using this approach. Focusing on one of the regions, which includes the model tumor suppressor RB1, we performed allelotyping of single-nucleotide polymorphic sites and identified a 1.34-Mb segment around RB1 characterized by a loss of polymorphism associated with the initial expansion of in situ neoplasia. This segment contains several positional candidate genes referred to by us as forerunner genes that may contribute to such expansion. We subsequently concentrated our efforts on the two neighbor genes flanking RB1, namely ITM2B and CHC1L, as well as P2RY5, which is located inside RB1. Here, we report that ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively, and thus by functional loss may contribute to the growth advantage of neoplasia. We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor