Batmunkh Munkhbat

Natural Selection and Population History in the Human Angiotensinogen Gene (AGT): 736 Complete AGT Sequences in Chromosomes from Around the World

Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A(-6) variant leads to the intriguing hypothesis that the G(-6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A(-6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A(-6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A(-6)G polymorphism. Further, haplotypes carrying the G(-6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G(-6) variant over the A(-6) variant in non-African populations. However, important localized effects may also be present.

Meta-Analysis Confirms the LCE3C_LCE3B Deletion as a Risk Factor for Psoriasis in Several Ethnic Groups and Finds Interaction with HLA-Cw6

A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletions association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

Alu insertion polymorphisms in Native Americans and related Asian populations

Background: Alu insertions provide useful markers for the study of inter-population affinities and historical processes, but data on these systems are not numerous in Native Americans and related populations. Aim: The study aimed to answer the following questions: (a) do the population relationships found agree with ethnic, historical and geographical data? and (b) what can heterozygote levels and associated results inform us about the events that led to the colonization of the New World? Subjects and methods: Twelve Alu insertion polymorphisms were studied in 330 individuals belonging to South American Native, Siberian and Mongolian populations. These data were integrated with those from 526 persons, to ascertain the relationships between Asian, Northern Arctic and Amerindian populations. Results: A decreasing trend concerning heterozygosities and amount of gene flow was observed in the three sets, in the order indicated above. Most results indicated the validity of these subdivisions. However, no clear structure could be observed within South American Natives, indicating the importance of dispersive (genetic drift, founder effects) factors in their differentiation. Conclusions: The answers to the questions are: (a) yes; and (b) an initial moderate bottleneck, intensified by more recent historical events (isolation and inbreeding), can explain the current Amerindian pattern of diversity.

Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice

TATA-box binding protein associated factor 1 (TAF1) protein is the largest and the essential component of the TFIID complex in the pathway of RNA polymerase II-mediated gene transcription, and it regulates transcription of a large number of genes related to cell division. The neuron-specific isoform of the TAF1 gene (N-TAF1), which we reported previously, may have an essential role in neurons through transcriptional regulation of many neuron-specific genes. In the present study, we cloned the full-length cDNA that encodes the mouse homologue of N-TAF1 (N-Taf1) protein. By carrying out of real time RT-PCR, we investigated the expression analysis of the N-Taf1 mRNA in mouse tissues and cell lines. As well as the human N-TAF1, the N-Taf1 showed limited expression in the brain and neuroblastoma, whereas Taf1 expressed elsewhere. Furthermore, in mouse embryo head or mouse brain, mRNA expression of TAF1 changes dramatically during development but N-Taf1 showed sustained expression. Our result suggests that the N-Taf1 gene has an important role in non-dividing neuronal cell rather than in cell division and proliferation during neurogenesis.

Genome-wide association analysis with selective genotyping identifies candidate loci for adult height at 8q21.13 and 15q22.33-q23 in Mongolians

We performed a genome-wide association study with 23,465 microsatellite markers to identify genes related to adult height. Selective genotyping was applied to extremely tall and extremely short individuals from the Khalkh-Mongolian population. Two loci, 8q21.13 and 15q22.33, which showed the strongest association with microsatellites were subjected to further analyses of SNPs in 782 tall and 773 short individuals. The most significant association was observed with SNP rs2220456 at 8q21.13 (Pxa0=xa00.000016). In the LD block at 15q22.32, SNP rs8038652 located in intron 1 of IQCH was strongly associated (Pxa0=xa00.0003), especially the AA genotype of the SNP under a recessive model was strongly associated with adult height (Pxa0=xa00.000046).

Intra- and intercontinental molecular variability of an Alu insertion in the 3' untranslated region of the LDLR gene

Abstract One-hundred three individuals from two Mongolian, two Siberian, and ten native American populations were studied in relation to a 340-bp sequence from an Alu insertion located in the 3 untranslated region of the LDLR gene. Seven haplotypes have been determined, and haplotype B1 was the most common, accounting for about half the sequences found. In general, diversity values are quite high, about 2.5 times higher than those found in other autosomal Alu sequences. Almost all (93%) of the variability occurs at the intrapopulation level, but the greatest among-group differentiation (6-8%) was found when we grouped in a single population all Native Americans plus Siberian Eskimos and Chukchi and compared them with Mongolians. This result is compatible with earlier mtDNA and Y-chromosome suggestions of a single origin for the first colonizers of the American continent. With this nuclear locus it was not possible to broadly distinguish between Central and South American natives. No evidence of selection or marked demographic changes was obtained with these data.

Divergence of East Asians and Europeans estimated using male- and female-specific genetic markers.

To study the male and female lineages of East Asian and European humans, we have sequenced 25 short tandem repeat markers on 453 Y-chromosomes and collected sequences of 72 complete mitochondrial genomes to construct independent phylogenetic trees for male and female lineages. The results indicate that East Asian individuals fall into two clades, one that includes East Asian individuals only and a second that contains East Asian and European individuals. Surprisingly, the European individuals did not form an independent clade, but branched within in the East Asians. We then estimated the divergence time of the root of the European clade as ∼41,000 years ago. These data indicate that, contrary to traditional views, Europeans diverged from East Asians around that time. We also address the origin of the Ainu lineage in northern Japan.

Case of a Mongolian child with extensive Mongolian spots in mucopolysaccharidosis type VI: Identification of a novel mutation in the arylsulfatase B gene

tin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Molec Genet 1998;7:1143–1148. 4 Spaunhurst KM, Hogendorf AM, Smith FJD et al. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Br J Dermatol 2012;166:875–878. 5 Eliason M, Leachman S, Feng B, Schwartz M, Hansen D. A review of the clinical phenotype of 254 patients with genetically confirmedpachyonychia congenita. J Am Acad Dermatol 2012;67:680–686.