| 其他摘要 | In human, LMBR1 (limb region 1 homolog (mouse)) gene locates in the chromosome 7q36, spanning about 210.2 kb and containing 17 exons which encode a 490-amino acids transmembrane protein. It has been found that the level of LMBR1 expression is associated with the digits number change of the vertebrate limbs. Furthermore, many mutations in the crucial element----intron 5 of this gene are associated with many phenotypes of preaxial polydactyly (PPD), as this region contains a long-range regulatory element of one gene associated with the development of skeleton system (SHH (sonic hedgehog) gene). This study aims to investigate the genetic diversity of the LMBR1 gene intron 5 , then to evaluate the sampling strategy of the HapMap and detect whether the region is subject to natural selection or not.
The International Haplotype Map Project (HapMap Project) was officially launched on October 2002, aiming to construct the genetic pattern of common variations in human genome. Since the first release, the HapMap data have been applied broadly in many fields, such as biological medicine, population genetics, etc. and contribute greatly to the research on genetic mechanisms of complex diseases and detection of natural selection and beyond. However, the representation of the HapMap samples needs to be evaluated.
In this study, we chose 41 East Asian individuals based on the information of geography and mitochondrial DNA haplogroups, and screened the single nucleotide polymorphisms (SNPs) n the LMBR1 intron 5. There is a significant difference between our data and the HapMap data, and the HapMap can not cover all common SNPs that we identified. Accordingly, we concluded that the strategy of choosing Chinese samples in the HapMap should be consummated.
Detection of natural selection would help to elucidate the evolutionary mechanisms, and also help to reveal the genetic mechanisms of complex diseases. Therefore, detection of natural selection is one of the hotspots in biology. Balancing selection, one type of nature selection, can maintain genetic polymorphism. Studies have reported many genes or regulatory sequence associated with diseases and particular phenotypes under balancing selection, e.g. G6PD gene, PTC gene, FMO gene, FSHB gene, and the 5’ regulatory region of CCR5 gene, etc.
This study found balancing selection on the 9256 bp region (Chr7: 156280954-156271699 (Build36)) of the LMBR1 intron 5 in 41 East Asian individuals, by Tajima’s D test and other population genetics analysis based on the single nucleotide polymorphisms. Further evidences of the balancing selection may be provided by the association between many mutations in LMBR1 intron 5 and many phenotypes of polydactyly, crucial role of the regulated SHH gene in the development of skeletal system, and the adaptive evolution of skeletal system.
In conclusion, this study provides an evaluation of the sampling strategy and data application of the HapMap project to some extent and furthermore, we identify that a gene regulatory element which is associated with development of skeletal system undergoes balancing selection. |
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