Additional file 1: of Structure and evolution of the filaggrin gene repeated region in primates

Additional tables and figures. (PDF 3.32 kb

Variants of <i>HOXB13</i> and <i>TRRAP</i> in the 59 small PC families.

<p>(A) Variant status of <i>HOXB13</i> and <i>TRRAP</i>. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable. (B) Results of Sanger-seq for shared variants of <i>HOXB13</i> and <i>TRRAP</i> (i) Heterozygous variant of <i>HOXB13</i> G132E (c.G395A) in GFPC024. (ii) Homozygous variant of <i>HOXB13</i> G132E (c.G395A) in GFPC079. (iii) Heterozygous variant of <i>TRRAP</i> C1217R (c.T3649C) in GFPC072. The positions of variants are indicated by red arrows. PC, prostate cancer.</p

Shared genes with variants.

<p>(A) Heat map of the shared genes with variants. Each column shows the family identification of large PC families or PC pairs of the small PC families. Each row shows the gene names and shared variants are filled with red (deleterious) or orange (nondeleterious) color. (B) Deleterious variants of the Cancer Gene Census genes. The variant status is shown. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable; PC, prostate cancer.</p

Shared genes with variants in the large PC families.

<p>(A) Twenty-two genes in the seven large families remained after filtering and prioritizing. Known susceptibility genes (<i>BRCA2</i> and <i>HOXB13</i>) and one novel gene (<i>TRRAP</i>) are shown by green rectangles. The combined scores of Exomiser are shown on the right side of the gene names. (B) Variant status of <i>BRCA2</i>, <i>HOXB13</i>, and <i>TRRAP</i>. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable. PC, prostate cancer.</p

Germline Variants of Prostate Cancer in Japanese Families

<div><p>Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, <i>BRCA2</i> and <i>HOXB13</i>. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, <i>BRCA2</i> and <i>HOXB13</i>, we identified <i>TRRAP</i> variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of <i>BRCA2</i>, <i>HOXB13</i>, and <i>TRRAP</i> from 59 additional small PC families (two patients per family). We identified two deleterious <i>HOXB13</i> variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (<i>ATP1A1</i>, <i>BRIP1</i>, <i>FANCA</i>, <i>FGFR3</i>, <i>FLT3</i>, <i>HOXD11</i>, <i>MUTYH</i>, <i>PDGFRA</i>, <i>SMARCA4</i>, and <i>TCF3</i>). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.</p></div

Pedigrees of the seven large PC families.

<p>Solid black rectangles represent affected patients with PC. Patients with PC analyzed by exome-seq were numbered (from 01 to 22). PC, prostate cancer.</p

Associations between clinical features and shared variant status.

<p>(A) Comparison of Gleason score between the shared families and unshared families. Gleason scores were averaged in each family. One family lacking Gleason score was omitted. (B) Comparison of age at diagnosis between the shared families and unshared families. Ages at diagnosis were averaged in each family. Shared, families with shared variants; unshared, families with unshared variants.</p

Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population

<div><p>The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (<i>HLA-A</i>, <i>-B</i>, <i>-C</i>, <i>-DRB1</i>, and <i>-DPB1</i>) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.</p> </div

The 10 most common five-locus HLA haplotypes in mainland Japanese.

†<p>Nine mainland groups (Hokkaido, Tohoku, Kanto, Hokuriku, Tokai, Kinki, Chugoku, Shikoku, and Kyushu) were combined.</p

Principal component analysis of 10 regional populations in Japan based on allele frequencies of five HLA loci.

<p>A) PCA plot, in which 10 Japanese district populations are plotted according to their corresponding eigenvectors of first and second principal components. B) PCS plot, in which HLA alleles are plotted according to their first and second principal component scores. Dotted lines correspond to mean ± one standard deviation of PCSs. HLA alleles whose absolute PCSs were greater than one standard deviation were selected, followed by Fisher's exact test to evaluate whether the allele frequencies were differentiated among regions. HLA alleles showing significant differentiation at <i>P</i><0.001 are determined as “ancestry informative HLA alleles” and labeled in the plot. The frequency distribution of the identified HLA alleles shows distinct patterns (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060793#pone-0060793-g003" target="_blank">Figure 3</a>). The HLA alleles showing similar pattern of differentiation are co-localized in the PCS plot. We marked HLA alleles showing similar patterns of differentiation (referred to as CL1-4) by circles.</p