The growth arrest special 5 (GAS5) is known to be involved in various cancers. However, its expression regulation remains unclear. Polymorphisms in the promoter region of GAS5 may affect its expression and be associated with cancer susceptibility. In this research, we first evaluated the association of a 5-base pair indel polymorphism (rs145204276) in the promoter region of GAS5 with hepatocelluar carcinoma (HCC) susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs145204276 significantly increased the risk of HCC in two independent case control sets (1034 HCC and 1054 controls). Further genotype-phenotype association analysis revealed that the deletion allele was markedly correlated with higher expression of GAS5 in HCC tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that the deletion allele improved an increased expression of GAS5 in three hepatoma cell lines. Intriguingly, overexpression of GAS5 displayed an anti-apoptosis effect in HCC cell lines, GAS5 knockdown could partially revert this anti-apoptosis effect, suggesting that GAS5 may act as a proto-oncogene in HCC, in contrast with its inhibitory role in other cancers. Further pyrosequencing revealed that the genotypes of rs145204276 were associated with methylation status of GAS5 promoter region. Taken together, our findings provided evidence that rs145204276 may contribute to hepatocarcinogenesis by affecting methylation status of the GAS5 promoter and subsequently its transcriptional activity thus serving as a potential therapy target for HCC.

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Polymorphisms in pre-miRNAs may affect its expression, then have effect on its target mRNAs and be associated with cancer susceptibility. In this study, we evaluated the association of an indel polymorphism rs57408770 in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. The contribution of rs57408770 to HCC risk was investigated in two independent case-control sets (1051 HCC and 1058 controls). Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. Moreover, the results of genotype-phenotype correlation analysis from both in vivo and in vitro experiments showed that the insertion allele was significantly correlated with higher expression of mature miR-3131 comparing with the deletion allele. The RNA-Binding Protein Immunoprecipitation assay results indicated that rs57408770 could affect the expression level of mature miR-3131 probably through disturbing the binding of splicing factor SRp20 with pre-miR-3131. Furthermore, overexpression of miR-3131 displayed a proliferation promoting and anti-apoptosis effect on HCC cell lines, suggesting that miR-3131 may act as a proto-oncogene in HCC. Finally, human genome-wide gene expression profile assay was used to screen the targets of miR-3131. The overexpressed miR-3131 could lead to a significant decrease of DTHD1 and XAF1 mRNA level. Taken together, our findings provided evidence that rs57408770 may play a functional role in the carcinogenesis of HCC by affecting SRp20 binding with pre-miR-3131 and affecting the expression of mature miR-3131, subsequently affecting the expression of DTHD1 and XAF1, thus confers risk for HCC.

AbstractArcheologically attested human occupation on the Tibet Plateau (TP) can be traced back to 160 thousand years ago (kya, Xiahe) via archaic people and 30~40 kya via anatomically modern human in Nwya Devu. However, the past human movements and peopling of the TP keep in its infancy in the modern/ancient DNA studies. Here, we performed the first modern/ancient genomic meta-analysis among 3,017 Paleolithic to present-day eastern Eurasian genomes (2,444 modern individuals from 183 populations (including 98 Ü-Tsang/Ando/Kham Tibetans) and 573 ancients (including 161 Chinese ancients first meta-analyzed here)). Closer genetic connection between ancient-modern highland Tibetans and lowland island/coastal Neolithic northern East Asians was identified, reflecting the main ancestry of high-altitude Tibeto-Burman speakers originated from the ancestors of Houli/Yangshao/Longshan ancients in the middle and lower Yellow River basin, consistent with the common North-China origin of Sino-Tibetan language and dispersal pattern of millet farmers. Although the shared common northern East Asian lineage between Tibetans and lowland East Asians, we still identified genetic differentiation between Highlanders and lowland northern East Asians, the former harboring more deeply diverged Hoabinhian/Onge ancestry and the latter possessing more modern Neolithic southern East Asian and Siberian ancestry, which suggested the co-existence of Paleolithic and Neolithic ancestries in modern and Neolithic East Asian Highlanders. Tibetans from Ü-Tsang/Ando/Kham Tibetan regions showed strong population stratifications consistent with their cultural backgrounds and geographic terrains (showed as barriers for human movements): stronger Chokhopani affinity in Ü-Tsang Tibetans, more western Eurasian ancestry in Ando and greater Neolithic southern East Asian ancestry in Kham Tibetan. Modern combined ancient genomes documented multiple waves of human migrations in TP past: the first layer of local Hunter-Gatherer mixed with Qijia Farmer arose the Chokhopani-associated Proto-Tibetan-Burman, admixture with the additional genetic materials from the western Eurasian steppe, Yellow River and Yangtze River respectively gave rise to modern Ando, Ü-Tsang and Kham Tibetans.

Mitochondrial DNA (mtDNA), coupled with maternal inheritance and relatively high mutation rates, provides a pivotal way for us to investigate the formation histories of populations. The Hui minority with Islamic faith is one of the most widely distributed ethnic groups in China. However, the exploration of Hui’s genetic architecture from the complete mitochondrial genome perspective has not been detected yet. Therefore, in this study, we employed the complete mitochondrial genomes of 98 healthy and unrelated individuals from Northwest China, as well as 99 previously published populations containing 7274 individuals from all over the world as reference data, to comprehensively dissect the matrilineal landscape of Hui group. Our results demonstrated that Hui group exhibited closer genetic relationships with Chinese Han populations from different regions, which was largely attributable to the widespread of haplogroups D4, D5, M7, B4, and F1 in these populations. The demographic expansion of Hui group might occur during the Late Pleistocene. Finally, we also found that Hui group might have gene exchanges with Uygur, Tibetan, and Tajik groups in different degrees and retain minor genetic imprint of European-specific lineages, therefore, hinting the existence of multi-ethnic integration events in shaping the genetic landscape of Chinese Hui group.

Due to the unique inheritance pattern, X-chromosomal short tandem repeats (X-STRs) have several advantages in complex kinship cases, such as deficiency cases or grandparent-grandchild and half-sisters testing. In our study, 541 unrelated individuals gathered from Mongolian and Eastern Chinese Han populations were successfully genotyped using the Investigator Argus X-12 kit. We calculated allele/haplotype frequencies and other forensic parameters of the two populations and further explored their genetic distance with already published Chinese populations and six global populations. Our results showed that the 12 X-STR markers were highly informative in the two populations when compared with nine other Chinese populations: significant differences were found at several loci. Geographically neighboring populations or different ethnic groups within the same area appeared to have closer evolutionary relationships. We also analyzed population genetic structure by performing clustering with the STRUCTURE program and Principal Coordinate Analysis (PCoA), and we found that the Chinese and other populations enrolled in this study could be distinguished. Furthermore, Mongolian males were distinguishable from the other studied males by a moderate genetic distance. Our study also expanded the X-STR database, which could facilitate the appropriate application of the 12 X-STR markers in the forensic field in China.

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