Ancestral Polymorphisms and Sex-Biased Migration Shaped the Demographic History of Brown Bears and Polar Bears

<div><p>Recent studies have reported discordant gene trees in the evolution of brown bears and polar bears. Genealogical histories are different among independent nuclear loci and between biparentally inherited autosomal DNA (aDNA) and matrilineal mitochondrial DNA (mtDNA). Based on multi-locus genomic sequences from aDNA and mtDNA, we inferred the population demography of brown and polar bears and found that brown bears have 6 times (aDNA) or more than 14 times (mtDNA) larger population sizes than polar bears and that polar bear lineage is derived from within brown bear diversity. In brown bears, the effective population size ratio of mtDNA to aDNA was at least 0.62, which deviated from the expected value of 0.25, suggesting matriarchal population due to female philopatry and male-biased migration. These results emphasize that ancestral polymorphisms and sex-biased migration may have contributed to conflicting branching patterns in brown and polar bears across aDNA genes and mtDNA.</p></div

Schematic topologies of aDNA gene trees from 13 loci.

<p>Based on the phylogenetic relationship between brown bears and polar bears (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078813#pone.0078813.s001" target="_blank">Figure S1</a>), gene trees are classified into paraphyletic, multi-furcating, and monophyletic topologies. The paraphyletic topology includes eight out of 13 loci (<i>ABCA1</i>, <i>SEL1L3</i>, <i>PREX2</i>, <i>SPTBN1</i>, <i>OSTA</i>, <i>CCDC90B</i>, <i>SPTA1</i>, and <i>IGSF22</i>). Only one locus, <i>AZIN1</i>, supports the monophyletic topology. The remaining four loci (<i>GGA3</i>, <i>ATP12A</i>, <i>TRAPPC10</i>, and <i>SCN5A</i>) are assigned into the multi-furcating topology.</p

Plots of the posterior mean and prior density <i>N</i>_uar, <i>N</i>_uma, and <i>T</i> estimated by kernel-ABC.

<p>The horizontal axis indicates the effective population size or number of generations, while the vertical axis indicates the density of prior distributions. The prior density is shown as a dashed line, with mean (<i>μ</i>) and variance (<i>μ</i>²). Ten different priors are distinguished by different colors and shown with <i>μ</i> values. Posterior means are shown as vertical solid lines, with colors corresponding to priors (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078813#pone.0078813.s006" target="_blank">Table S2</a>).</p

Posterior estimates of three demographic parameters.

a<p>Distribution of posterior means for each parameter generated from 100 replications with 20,000 simulated samples.</p>b<p>Effective population size based on aDNA is expressed as <i>N</i>_e individuals.</p>c<p>Ratio of <i>N</i>_e based on mtDNA to aDNA was calculated by <i>N</i>_mtDNA/2<i>N</i>_e.</p

Demographic histories of brown and polar bears based on (A) aDNA and (B) mtDNA.

<p>(A) Parameters were estimated by kernel-ABC with the sequence data from brown bears (2<i>n</i> = 36) and polar bears (2<i>n</i> = 36) for 14 loci. The effective population size based on aDNA (<i>N</i>_aDNA-uar = 92,868 or <i>N</i>_aDNA-uma = 15,734) is twice the size of <i>N</i>_uar = 46,434 or <i>N</i>_uma = 7,867. Similarly, (B) demographic parameters were estimated from the Set-I dataset (8,268 bp from four brown bears and 10 polar bears). Parameters based on the Set-II dataset (15,403 bp from nine brown bears and 26 polar bears) are shown in parentheses. mtDNA genealogy is based on the results from the Set-I dataset. <i>T</i>_MRCA estimates are plotted on each MRCA between each of the geographic lineages in brown bears and the ancestral polar bear lineage (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078813#pone.0078813.s003" target="_blank">Figure S3</a>).</p

Enzyme Activities of CYP1A and CYP1B1 alleles

Raw and relative enzyme activities of CYP1A and CYP1B1 allele

F2_Phenotype_and_Genotype_data

Raw morphological data, genetic sex, and CYP1B1 genotypes from F2 individuals

Morphological data from two medaka populations

Raw morphological data from Tanabe and Maegok populations

Mapping Variation in Cellular and Transcriptional Response to 1,25-Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells

<div><p>The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (I_max) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10⁻⁸) and rs6451692 on chromosome 5 (p = 2.55 x 10⁻⁸), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, <i>CCL28</i>, and the translation initiation gene, <i>PAIP1</i>. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (<i>ETV3L</i>) and EH-domain containing 4 (<i>EHD4</i>). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (<i>FRMD6</i>), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of I_max and the response eQTL mapping enabled identification of putative I_max-associated candidate genes such as <i>PAIP1</i> and the transcriptional repressor gene <i>ZNF649</i>. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis.</p></div

Associations between SNPs in vitamin D receptor (VDR) binding sites and transcriptional response.

<p>(<b>A</b>) Boxplots showing the effect of genotype on log₂ fold change of <i>FRMD6</i> and <i>KIAA1211</i> transcript levels, with genotypes of the associated SNPs on the x-axis. (<b>B</b>) Location of SNPs associated with transcription response of <i>FRMD6</i> (rs3783273, top panel) and <i>KIAA1211</i> (rs7698085, bottom panel) within VDR binding sites, indicated by the gray horizontal arrows. The SNP locations are indicated by the vertical orange arrows. VDR binding site information was obtained from a published ChIP-seq dataset from THP-1 monocytic cells treated with 1,25D and bacterial lipopolysaccharide (LPS).</p