Iterative pruning PCA improves resolution of highly structured populations

Background  

Non-random patterns of genetic variation exist among individuals in a population owing to a variety of evolutionary factors. Therefore, populations are structured into genetically distinct subpopulations. As genotypic datasets become ever larger, it is increasingly difficult to correctly estimate the number of subpopulations and assign individuals to them. The computationally efficient non-parametric, chiefly Principal Components Analysis (PCA)-based methods are thus becoming increasingly relied upon for population structure analysis. Current PCA-based methods can accurately detect structure; however, the accuracy in resolving subpopulations and assigning individuals to them is wanting. When subpopulations are closely related to one another, they overlap in PCA space and appear as a conglomerate. This problem is exacerbated when some subpopulations in the dataset are genetically far removed from others. We propose a novel PCA-based framework which addresses this shortcoming.     

Insight into the Peopling of Mainland Southeast Asia from Thai Population Genetic Structure

There is considerable ethno-linguistic and genetic variation among human populations in Asia, although tracing the origins of this diversity is complicated by migration events. Thailand is at the center of Mainland Southeast Asia (MSEA), a region within Asia that has not been extensively studied. Genetic substructure may exist in the Thai population, since waves of migration from southern China throughout its recent history may have contributed to substantial gene flow. Autosomal SNP data were collated for 438,503 markers from 992 Thai individuals. Using the available self-reported regional origin, four Thai subpopulations genetically distinct from each other and from other Asian populations were resolved by Neighbor-Joining analysis using a 41,569 marker subset. Using an independent Principal Components-based unsupervised clustering approach, four major MSEA subpopulations were resolved in which regional bias was apparent. A major ancestry component was common to these MSEA subpopulations and distinguishes them from other Asian subpopulations. On the other hand, these MSEA subpopulations were admixed with other ancestries, in particular one shared with Chinese. Subpopulation clustering using only Thai individuals and the complete marker set resolved four subpopulations, which are distributed differently across Thailand. A Sino-Thai subpopulation was concentrated in the Central region of Thailand, although this constituted a minority in an otherwise diverse region. Among the most highly differentiated markers which distinguish the Thai subpopulations, several map to regions known to affect phenotypic traits such as skin pigmentation and susceptibility to common diseases. The subpopulation patterns elucidated have important implications for evolutionary and medical genetics. The subpopulation structure within Thailand may reflect the contributions of different migrants throughout the history of MSEA. The information will also be important for genetic association studies to account for population-structure confounding effects.     

Detecting purely epistatic multi-locus interactions by an omnibus permutation test on ensembles of two-locus analyses

Background  

Purely epistatic multi-locus interactions cannot generally be detected via single-locus analysis in case-control studies of complex diseases. Recently, many two-locus and multi-locus analysis techniques have been shown to be promising for the epistasis detection. However, exhaustive multi-locus analysis requires prohibitively large computational efforts when problems involve large-scale or genome-wide data. Furthermore, there is no explicit proof that a combination of multiple two-locus analyses can lead to the correct identification of multi-locus interactions.     

HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies

Recently a newly identified clinical syndrome of disseminated non-tuberculous mycobacterial diseases (with or without other opportunistic infections in adult patients who were previously healthy, has been recognized in association with an acquired autoantibody to interferon-gamma. This syndrome is emerging as an important cause of morbidity and mortality, especially among people of Asian descent. Trigger for the production of this autoantibody remains unknown, but genetic factors are strongly suspected to be involved. We compared HLA genotyping between 32 patients with this clinical syndrome, and 38 controls. We found that this clinical syndrome was associated with very limited allele polymorphism, with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02. Odds ratio of DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02 were 7.03 (95% CI, 2.18–22.69, P<0.0001, 9.06 (95% CI, 2.79–29.46, P<0.0001), 6.68 (95% CI, 2.29–19.52, P = 0.0004), and 6.64 (95% CI, 2.30–19.20, P = 0.0004), respectively. Further investigation is warranted to provide better understanding on pathogenesis of this association.     

PanSNPdb: the Pan-Asian SNP genotyping database

The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP.     

Microbial Ecology of Thailand Tsunami and Non-Tsunami Affected Terrestrials

The effects of tsunamis on microbial ecologies have been ill-defined, especially in Phang Nga province, Thailand. This ecosystem was catastrophically impacted by the 2004 Indian Ocean tsunami as well as the 600 year-old tsunami in Phra Thong island, Phang Nga province. No study has been conducted to elucidate their effects on microbial ecology. This study represents the first to elucidate their effects on microbial ecology. We utilized metagenomics with 16S and 18S rDNA-barcoded pyrosequencing to obtain prokaryotic and eukaryotic profiles for this terrestrial site, tsunami affected (S₁), as well as a parallel unaffected terrestrial site, non-tsunami affected (S₂). S₁ demonstrated unique microbial community patterns than S₂. The dendrogram constructed using the prokaryotic profiles supported the unique S₁ microbial communities. S₁ contained more proportions of archaea and bacteria domains, specifically species belonging to Bacteroidetes became more frequent, in replacing of the other typical floras like Proteobacteria, Acidobacteria and Basidiomycota. Pathogenic microbes, including Acinetobacter haemolyticus, Flavobacterium spp. and Photobacterium spp., were also found frequently in S₁. Furthermore, different metabolic potentials highlighted this microbial community change could impact the functional ecology of the site. Moreover, the habitat prediction based on percent of species indicators for marine, brackish, freshwater and terrestrial niches pointed the S₁ to largely comprise marine habitat indicating-species.     

Molecular dynamics simulations reveal structural instability of human trypsin inhibitor upon D50E and Y54H mutations

Serine protease inhibitor Kazal type 1 (SPINK1) plays an important role in protecting the pancreas against premature trypsinogen activation that causes pancreatitis. Various mutations in the SPINK1 gene were shown to be associated with patients with pancreatitis. Recent transfection studies identified intracellular folding defects, probably caused by mutation induced misfolding of D50E and Y54H mutations, as a common mechanism that reduces SPINK1 secretion and as a possible novel mechanism of SPINK1 deficiency associated with chronic pancreatitis. Using molecular dynamics, we investigated the effects of D50E and Y54H mutations on SPINK1 dynamics and conformation at 300 K. We found that the structures of D50E and Y54H mutants were less stable than and were distorted from those of the wild type, as indicated by the RMSD plots, RMSF plots and DSSP series. Specifically, unwinding of the top of helices (the main secondary structures) and the distortion of the loops above the helices were observed. It may be possible that this distorted protein structure may be recognized as “non-native” by members of the chaperone family; it may be further retained and targeted for degradation, leading to SPINK1 secretion reduction and subsequently pancreatitis in patients as Király et al. (Gut 56:1433, 2007) proposed.