Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structura predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G>A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an α-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe pheno- types can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domainand the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides po- tential evidence for a possible correlation between the severity of the phenotypes of HSP with the ex- tension of the changes in the protein structures of atlastin.
CHEN SuqinZHOU YanLI XunhuaLabuHUANG ShuangHUANG WeijunZHOU ChunlongMAXWELL Patrick HWANG Yiming
Genomic variation is the genetic basis of phenotypic diversity among individuals, including variation in disease susceptibility and drug response. The greatest promise of the International HapMap is to provide roadmaps for identifying genetic variants predisposing to complex diseases. Single nucleotide polymorphism (SNP) is the fundamental element of the HapMap. Allele frequency of SNPs is one of the major factors affecting the resulting HapMap, being the factor upon which linkage disequilibrium (LD) is calculated, haplotypes are constructed, and tagging SNPs (tagSNPs) are selected. The cutoff thresholds for the frequency of minor alleles used in the making of the map therefore have profound effects on the resolution of that map. To date most researchers have adopted their own cutoff thresholds, and there has been little real dataset-based evaluation of the effects of different cutoff thresholds on HapMap resolution. In an attempt to assess the implications of different cutoff values, we analyzed our own data for the centromeric genes on Chromosome 15 in Chinese Han and Tibetan populations, with respect to minor allele frequency cutoff values of ≥0.01 (0.01 group), ≥0.05 (0.05 group), and ≥0.10 (0.10 group), and constructed HapMaps from each of the datasets. The resolution, study power and cost-effectiveness for each of the maps were compared. Our results show that the 0.01 threshold pro- vides the greatest power (P = 0.019 in Han and P = 0.029 in Tibetan for 0.01 vs. 0.05 threshold) and detects most population-specific haploypes (P = 0.012 for 0.01 vs. 0.05 threshold). However, in the regions studied, the 0.05 cutoff threshold did not significantly increase power above the 0.10 threshold (P = 0.191 in Han; 1.000 in Tibetans), and did not improve resolution over the 0.10 value for population-specific haplotypes (P = 0.592) neither. Furthermore the 0.05 and 0.10 values produced the same figures for tagging efficiency, LD block number, LD length, study power and cost-savings in the Tibetan population. These r
Genetic variations and their functional implications have been one of the focuses in recent genome research. With the release of the HapMap by the International Consortium, and the availability of the ultra-high-volume genotyping platform, it will soon be possible to use genome-wide association ap- proach to identify genetic variations responsible for complex traits/diseases. While the power of this ap- proach is generally agreed, it is a debated issue as to how much population difference should be exploited, and how best it should be applied. To address this issue we have sequenced 7 genes in the centromeric region of chromosome 15, investigated their SNPs, SNP frequencies, tagSNPs, LD structures, and hap- lotypes in 50 Tibetan subjects, and compared them with those from the Han population. Genetic diversi- ties between the two populations were also quantified. Our results show that the overall genetic variation between the two populations is very little, but there are differences, primarily in allele frequencies, which is a dominating factor for haplotypes and tagSNPs. In general Tibetans have longer LD and less diversity inthe region studied. These data provide genetic evi- dence for the close relationship between the two populations, and support the idea that all populations are fundamentally the same, but also indicate popu- lation variations, particularly in allele frequency, should be taken into account in complex traits/ dis- eases analysis. Data obtained in this investigation not only help us understand the genome region, but also provide road maps for variation study in the genes/ region in Tibetan population.
