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Comparative Genomics

Dr. Bing Su, principal investigator, The enlarged brain and highly developed cognitive skills are the most significant characteristics that set us apart from our relatives, the non-human primates. This evolutionary expansion is believed to be crucial to the highly developed cognitive abilities in humans, yet its genetic basis remains unsolved. our laboratory focuses on (1) the genetic mechanism underlying the dramatic enlargement of human brain and its highly developed cognitive skills during human evolution; (2) Origins and migration of modern human populations in East Asia and its adaptation to environmental stress.

1. Genetic evidence of Paleolithic colonization and Neolithic expansion of modern humans on the Tibetan Plateau

Tibetans live on the highest plateau in the world, their current population size is nearly 5 million, and most of them live at an altitude exceeding 3,500 meters. Therefore, the Tibetan Plateau is a remarkable area for cultural and biological studies of human population histories. However, the chronological profile of the Tibetan Plateau’s colonization remains an unsolved question of human prehistory. To reconstruct the prehistoric colonization and demographic history of modern humans on the Tibetan Plateau, we systematically sampled 6,109 Tibetan individuals from 41 geographic populations across the entire region of the Tibetan Plateau and analyzed the phylogeographic patterns of both paternal (n = 2,354) and maternal (n = 6,109) lineages as well as genome-wide SNP markers (n = 50) in Tibetan populations. We found that there have been two distinct, major prehistoric migrations of modern humans into the Tibetan Plateau. The first migration was marked by ancient Tibetan genetic signatures dated to around 30,000 years ago, indicating that the initial peopling of the Tibetan Plateau by modern humans occurred during the Upper Paleolithic rather than Neolithic. We also found evidences for relatively young (only 7-10 thousand years old) shared Y chromosome and mitochondrial DNA haplotypes between Tibetans and Han Chinese, suggesting a second wave of migration during the early Neolithic. Collectively, the genetic data indicate that Tibetans have been adapted to a high altitude environment since initial colonization of the Tibetan Plateau in the early Upper Paleolithic, before the Last Glacial Maximum, followed by a rapid population expansion that coincided with the establishment of farming and yak pastoralism on the Plateau in the early Neolithic.Molecular Biology and Evolution 2013, 30(8):1761-1778; Molecular Biology and Evolution 2013, 30(8):1889-1898

2. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10−5, odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10−6). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.Molecular Psychiatry advance online publication 9 April 2013;doi: 10.1038/mp.2013.37


Selected Publications

1.  Zhang X, Qi X, Yang Z, Shi H, Su B* 2013. Analysis of mitochondrial genome diversity identifies new and ancient maternal lineages in Cambodian aborigines. Nat Commun 4: 2599.

2.  Qi X, Cui C, Peng Y, Zhang X, Yang Z, ….., Su B* 2013. Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau. MolBiolEvol 30: 1761-1778.

3.  Xiang K, Ouzhuluobu, Peng Y, ….., Qi X*, Su B* 2013. Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. MolBiolEvol 30: 1889-1898.

4.  Li M, Luo XJ, ….., Su B.* 2013. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. Mol Psychiatry. doi: 10.1038/mp.2013.73

5.  Shi L, Lin Q, Su B* 2013. Human-Specific Hypomethylation of CENPJ, a Key Brain Size Regulator. MolBiolEvol.

6.  Li M, Ge T, Feng J, Su B* 2013. SLC6A15 rs1545843 and depression: implications from brain imaging data. Am J Psychiatry 170: 805.

7.  Li M, Su B* 2013. Up-regulation of NOTCH4 gene expression in bipolar disorder: future studies. Am J Psychiatry 170: 560-561.

8.  Shi L, Li M, Lin Q, Qi X, Su B* 2013. Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans. BMC Biology 11: 62.

9.  Sun Z, Zhang Y, Zhang R, Qi X, Su B* 2013. Functional divergence of the rapidly evolving miR-513 subfamily in primates. BMC EvolBiol 13: 255.

Lab Staff


Dr. Hong ShiAssociate

Dr. Xue-Bin Qi, Associate Professor,

Ms. Hui Zhang, Research Associate,

Ms. Yan Guo, Research Associate,

Dr. Yi Peng, PhD. Research Assistant

Dr. Lei Shi, PhD. Research Assistant

Graduate Students:


Xiong-Jian Luo, 2005; Jing-Kai Wang, 2005; Ruo-Lin Yang, 2005; Ling Huang, 2005; Leng Han, 2005; Ao-Lei Niu, 2006; Zheng-Hua Sun, 2006; Yi Peng, 2007; Lei Shi, 2007; Yan-Feng Zhang, 2007; Ming Li, 2008; Li-Xin Yang, 2008; Ying-Mei Peng, 2008; Zhao-Hui Yang, 2009; Xiang-Yu Cao, 2009; Kun Xiang, 2010; Yi Wang, 2010; Xu Zhang, 2010; Qiang Lin, 2011;

Jie-Wei Liu, 2012; Yan-Dong Yang, 2012; Shi-Yu Liao, 2012; Xin Luo, 2013; Yi-Bo He, 2013


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