Cui, T. | bioRxiv Science

bioRxiv2018

Genome-wide CNV study and functional evaluation identified CTDSPL as tumour suppressor gene for cervical cancer

We have investigated copy number variations (CNVs) in relation to cervical cancer by analyzing 731,422 single-nucleotide polymorphisms (SNPs) in 1,034 cervical cancer cases and 3,948 controls, followed by replication in 1,396 cases and 1,057 controls. We found that a 6367bp deletion in intron 1 of the CTD small phosphatase like gene (CTDSPL) was associated with 2.54-fold increased risk of cervical cancer (odds ratio =2.54, 95% confidence interval =2.08-3.12, P=2.0x10-19). This CNV is one of the strongest genetic risk variants identified so far for cervical cancer. The deletion removes the binding sites of zinc finger protein 263, binding protein 2 and interferon regulatory factor 1, and hence downregulates the transcription of CTDSPL. HeLa cells expressing CTDSPL showed a significant decrease in colony-forming ability. Compared with control groups, mice injected with HeLa cells expressing CTDSPL exhibited a significant reduction in tumour volume. Furthermore, CTDSPL-depleted immortalized End1/E6E7 could form tumours in NOD-SCID mice.

cancer biology↗

bioRxiv2017

Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World

BackgroundThe metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (> 20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. Fatty acid desaturase (FADS) 1 and 2 catalyze the rate-limiting steps in the biosynthesis of LC-PUFAs. The FADS region contains two haplotypes; ancestral and derived, where the derived haplotypes are associated with more efficient LC-PUFA biosynthesis and is nearly fixed in Africa. In addition, Native American populations appear to be nearly fixed for the lesser efficient ancestral haplotype, which could be a public health problem due to associated low LC-PUFA levels, while Eurasia is polymorphic. This haplotype frequency distribution is suggestive of archaic re-introduction of the ancestral haplotype to non-African populations or ancient polymorphism with differential selection patterns across the globe. Therefore, we tested the FADS region for archaic introgression or ancient polymorphism. We specifically addressed the genetic architecture of the FADS region in Native American populations to better understand this potential public health impact.\n\nResultsWe confirmed Native American ancestry is nearly fixed for the ancestral haplotype and is under positive selection. The ancestral haplotype frequency is also correlated to Siberian populations geographic location further suggesting the ancestral haplotype s role in cold weather adaptation and leading to the high haplotype frequency within Native American populations. We also find that the Neanderthal is more closely related to the derived haplotypes while the Denisovan clusters closer to the ancestral haplotypes. In addition, the derived haplotypes have a time to the most recent common ancestor of 688,474 years ago which is within the range of the modern-archaic hominin divergence.\n\nConclusionsThese results support an ancient polymorphism forming in the FADS gene region with differential selection pressures acting on the derived and ancestral haplotypes due to the old age of the derived haplotypes and the ancestral haplotype being under positive selection in Native American ancestry populations. Further, the near fixation of the less efficient ancestral haplotype in Native American ancestry suggests the need for future studies to explore the potential health risk of associated low LC-PUFA levels in Native American ancestry populations.

evolutionary biology↗