We analyzed genome-wide single-nucleotide polymorphism data of 11,069 Japanese individuals recruited from all 47 prefectures of Japan to clarify their genetic structure. The principal component ...analysis at the prefectural level enabled us to study the relationship between geographical location and genetic differentiation. The results revealed that the mainland Japanese were not genetically homogeneous, and the genetic structure could be explained mainly by the degree of Jomon ancestry and the geographical location. One of the interesting findings was that individuals in the Shikoku region (i.e., Tokushima Prefecture, Kagawa Prefecture, Ehime Prefecture, and Kochi Prefecture) were genetically close to Han Chinese. Therefore, the genetic components of immigrants from continental East Asia in the Yayoi period may have been well maintained in Shikoku. The present results will be useful for understanding the peopling of Japan, and also provide suggestions for recruiting subjects in genetic association studies.
A geographical gradient of height has existed in Japan for approximately 100 years. People in northern Japan tend to be taller than those in southern Japan. The differences in annual temperature and ...day length between the northern and southern prefectures of Japan have been suggested as possible causes of the height gradient. Although height is well known to be a polygenic trait with high heritability, the genetic contributions to the gradient have not yet been explored. Polygenic score (PS) is calculated by aggregating the effects of genetic variants identified by genome-wide association studies (GWASs) to predict the traits of individual subjects. Here, we calculated the PS of height for 10,840 Japanese individuals from all 47 prefectures in Japan. The median height PS for each prefecture was significantly correlated with the mean height of females and males obtained from another independent Japanese nation-wide height dataset, suggesting genetic contribution to the observed height gradient. We also found that individuals and prefectures genetically closer to continental East Asian ancestry tended to have a higher PS; modern Japanese people are considered to have originated as result of admixture between indigenous Jomon people and immigrants from continental East Asia. Another PS analysis based on the GWAS using only the mainland Japanese was conducted to evaluate the effect of population stratification on PS. The result also supported genetic contribution to height, and indicated that the PS might be affected by a bias due to population stratification even in a relatively homogenous population like Japanese.
Modern Japanese people have two major ancestral populations: indigenous Jomon hunter-gatherers and continental East Asian farmers. To determine the formation process of the current Japanese ...population, we developed a detection method for variants derived from ancestral populations using a summary statistic, the ancestry marker index (AMI). We applied AMI to modern Japanese population samples and identified 208,648 single nucleotide polymorphisms (SNPs) that were likely derived from the Jomon people (Jomon-derived variants). Analysis of Jomon-derived variants in 10,842 modern Japanese individuals recruited from all over Japan revealed that the admixture proportions of the Jomon people varied between prefectures, probably owing to the prehistoric population size difference. The estimated allele frequencies of genome-wide SNPs in the ancestral populations of the modern Japanese suggested their adaptive phenotypic characteristics to their respective livelihoods. Based on our findings, we propose a formation model for the genotypic and phenotypic gradations of the current Japanese archipelago populations.
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•We developed a detection tool for ancestry-derived variants in an admixed population•The ancestral admixture proportion varied among Japanese prefectures•Japanese ancestries had adaptive phenotypes to their respective livelihoods•We propose a formation model for the regional gradations of the current Japanese
Biological sciences; Genetics; Genomics; Human Genetics
The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there ...is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polymorphisms within HLA gene loci are strongly associated with susceptibility to autoimmune disorders; however, it is not clear how genetic variations in these loci confer a disease risk. Here, we ...devised a cell-surface MHC expression assay to detect allelic differences in the intrinsic stability of HLA-DQ proteins. We found extreme variation in cell-surface MHC density among HLA-DQ alleles, indicating a dynamic allelic hierarchy in the intrinsic stability of HLA-DQ proteins. Using the case-control data for type 1 diabetes (T1D) for the Swedish and Japanese populations, we determined that T1D risk-associated HLA-DQ haplotypes, which also increase risk for autoimmune endocrinopathies and other autoimmune disorders, encode unstable proteins, whereas the T1D-protective haplotypes encode the most stable HLA-DQ proteins. Among the amino acid variants of HLA-DQ, alterations in 47α, the residue that is located on the outside of the peptide-binding groove and acts as a key stability regulator, showed strong association with T1D. Evolutionary analysis suggested that 47α variants have been the target of positive diversifying selection. Our study demonstrates a steep allelic hierarchy in the intrinsic stability of HLA-DQ that is associated with T1D risk and protection, suggesting that HLA instability mediates the development of autoimmune disorders.
Because ≈90% of malaria cases occur in Africa, emergence of artemisinin-resistant Plasmodium falciparum in Africa poses a serious public health threat. To assess emergence of artemisinin-resistant ...parasites in Uganda during 2014-2016, we used the recently developed ex vivo ring-stage survival assay, which estimates ring-stage-specific P. falciparum susceptibility to artemisinin. We conducted 4 cross-sectional surveys to assess artemisinin sensitivity in Gulu, Uganda. Among 194 isolates, survival rates (ratio of viable drug-exposed parasites to drug-nonexposed controls) were high (>10%) for 4 isolates. Similar rates have been closely associated with delayed parasite clearance after drug treatment and are considered to be a proxy for the artemisinin-resistant phenotype. Of these, the PfKelch13 mutation was observed in only 1 isolate, A675V. Population genetics analysis suggested that these possibly artemisinin-resistant isolates originated in Africa. Large-scale surveillance of possibly artemisinin-resistant parasites in Africa would provide useful information about treatment outcomes and help regional malaria control.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A previous study reported that some of the human leukocyte antigen (
HLA
) alleles and haplotypes in present-day humans were acquired by admixture with archaic humans; specifically, an exceptionally ...diverged
HLA-B*73
allele was proposed to be transmitted from Denisovans, although the DNA sequence of
HLA-B*73
has not been detected in the Denisovan genome. Here, we argue against the hypothesis that
HLA-B*73
introgressed from Denisovans into early modern humans. A phylogenetic analysis revealed that
HLA-B*73:01
formed a monophyletic group with a chimpanzee
MHC-B
allele, strongly suggesting that the
HLA-B*73
allelic lineage has been maintained in humans as well as in chimpanzees since the divergence of humans and chimpanzees. The global distribution of
HLA-B*73
allele showed that the population frequency of
HLA-B*73
in west Asia (0.24 %)—a possible site of admixture with Denisovans—is lower than that in Europe (0.72 %) and in south Asia (0.69 %). Furthermore,
HLA-B*73
is not observed in Melanesia even though the Melanesian genome contains the highest proportion of Denisovan ancestry in present-day human populations. Single nucleotide polymorphisms in
HLA-A*11
-
HLA-C*12:02
or
HLA-A*11
-
C*15
haplotypes, one of which was assumed to be transmitted together with
HLA-B*73
from Denisovans by the study of Abi-Rached and colleagues, were not differentiated from those in other
HLA-A-C
haplotypes in modern humans. These results do not support the introgression hypothesis. Thus, we conclude that it is highly likely that
HLA-B*73
allelic lineage has been maintained in the direct ancestors of modern humans.
Approximately 5‐10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, ...host genetic factors behind low immune response to this HB vaccine were investigated by a genome‐wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome‐wide SNP typing data. The GWAS identified independent associations of HLA‐DRB1‐DQB1, HLA‐DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA‐DRB1‐DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1‐DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1‐DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1‐DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA‐DR‐DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR‐DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).
Mapping Human Genetic Diversity in Asia Abdulla, Mahmood Ameen; Ahmed, Ikhlak; Assawamakin, Anunchai ...
Science (American Association for the Advancement of Science),
12/2009, Letnik:
326, Številka:
5959
Journal Article
Recenzirano
Odprti dostop
Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal ...variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.
Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 ...show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.
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