Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To d...Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.展开更多
Protein evolution proceeds by two distinct processes： 1） individual mutation and selection for adaptive mutations and 2） rearrangement of entire domains within proteins into novel combinations, producing new protei...Protein evolution proceeds by two distinct processes： 1） individual mutation and selection for adaptive mutations and 2） rearrangement of entire domains within proteins into novel combinations, producing new protein families that combine functional properties in ways that previously did not exist. Domain rearrangement poses a challenge to sequence alignment-based search methods, such as BLAST, in predicting homology since the methodology implicitly assumes that related proteins primarily differ from each other by individual mutations. Moreover, there is ample evidence that the evolutionary process has used （and continues to use） domains as building blocks, therefore, it seems fit to utilize computational, domain-based methods to reconstruct that process. A challenge and opportunity for computational biology is how to use knowledge of evolutionary domain recombination to characterize families of proteins whose evolutionary history includes such recombination, to discover novel proteins, and to infer protein-protein interactions. In this paper we review techniques and databases that exploit our growing knowledge of “horizontal” protein evolution, and suggest possible areas of future development. We illustrate the power of the domain-based methods and the possible directions of future development by a case history in progress aiming at facilitating a particular approach to understanding microbial pathogenicity.展开更多
基金supported by the grant from the Youth National Science Foundation of China (No.31100908)
文摘Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.
基金supported by NSF of USA under Grant Nos. 0835718 and 0235792NIH under Grant Nos. 5PN2EY016570-06 and5R01NS063405-02+2 种基金the Beckman Institute for Advanced Science and Technologythe National Center for Supercomputing Applicationsthe Renaissance Computing Institute
文摘Protein evolution proceeds by two distinct processes： 1） individual mutation and selection for adaptive mutations and 2） rearrangement of entire domains within proteins into novel combinations, producing new protein families that combine functional properties in ways that previously did not exist. Domain rearrangement poses a challenge to sequence alignment-based search methods, such as BLAST, in predicting homology since the methodology implicitly assumes that related proteins primarily differ from each other by individual mutations. Moreover, there is ample evidence that the evolutionary process has used （and continues to use） domains as building blocks, therefore, it seems fit to utilize computational, domain-based methods to reconstruct that process. A challenge and opportunity for computational biology is how to use knowledge of evolutionary domain recombination to characterize families of proteins whose evolutionary history includes such recombination, to discover novel proteins, and to infer protein-protein interactions. In this paper we review techniques and databases that exploit our growing knowledge of “horizontal” protein evolution, and suggest possible areas of future development. We illustrate the power of the domain-based methods and the possible directions of future development by a case history in progress aiming at facilitating a particular approach to understanding microbial pathogenicity.
