Bayesian tip-dated phylogeny and biogeography of Cissampelideae (Menispermaceae): Mitigating the effects of homoplastic morphological characters.

The integration of morphological and molecular data is essential to understand the affinities of fossil taxa and spatio-temporal evolutionary processes of organisms. However, homoplastic morphological characters can mislead the placement of fossil taxa and impact downstream analyses. Here, we provide an example of how to mitigate effectively the effect of morphological homoplasy on the placement of fossil taxa and biogeographic inferences of Cissampelideae. We assembled three data types, morphological data only, morphological data with a molecular scaffold and combined morphological and molecular data. By removing high-level homoplastic morphological data or reweighting the morphological characters, we conducted 15 parsimony, 12 undated Bayesian and four dated Bayesian analyses. Our results show that the 14 selected Cissampelideae fossil taxa are placed poorly when based only on morphological data, but the addition of molecular scaffold and combination of morphological and molecular data greatly improve the resolution of fossil nodes. We raise the monotypic Stephania subg. Botryodiscia to generic status and discover that three fossils previously assigned to Stephania should be members of Diploclisia. The Bayesian tip-dated tree recovered by removing homoplastic morphological characters with a Rescaled Consistency Index <0.25 has the highest stratigraphic fit and consequently generates more reasonable biogeographic reconstruction for Cissampelideae. Cissampelideae began to diversify in Asia in the latest Cretaceous and subsequently dispersed to South America around the Cretaceous-Palaeogene boundary. Two dispersal events from Asia to Africa occurred in the Early Eocene and the Late Eocene-Late Oligocene, respectively. These findings provide guidelines and practical methods for mitigating the effects of homoplastic morphological characters on fossil placements and Bayesian tip-dating, as well as insights into the past tropical floristic exchanges among different continents.

Brain Growth Charts for Quantitative Analysis of Pediatric Clinical Brain MRI Scans with Limited Imaging Pathology.

Background Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. These barriers have curtailed retrospective studies of clinical brain MRI scans compared with more costly prospectively acquired research-quality brain MRI scans. Purpose To provide a benchmark for neuroanatomic variability in clinically acquired brain MRI scans with limited imaging pathology (SLIPs) and to evaluate if growth charts from curated clinical MRI scans differed from research-quality MRI scans or were influenced by clinical indication for the scan. Materials and Methods In this secondary analysis of preexisting data, clinical brain MRI SLIPs from an urban pediatric health care system (individuals aged ≤22 years) were scanned across nine 3.0-T MRI scanners. The curation process included manual review of signed radiology reports and automated and manual quality review of images without gross pathology. Global and regional volumetric imaging phenotypes were measured using two image segmentation pipelines, and clinical brain growth charts were quantitatively compared with charts derived from a large set of research controls in the same age range by means of Pearson correlation and age at peak volume. Results The curated clinical data set included 532 patients (277 male; median age, 10 years [IQR, 5-14 years]; age range, 28 days after birth to 22 years) scanned between 2005 and 2020. Clinical brain growth charts were highly correlated with growth charts derived from research data sets (22 studies, 8346 individuals [4947 male]; age range, 152 days after birth to 22 years) in terms of normative developmental trajectories predicted by the models (median r = 0.979). Conclusion The clinical indication of the scans did not significantly bias the output of clinical brain charts. Brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement research data sets. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ertl-Wagner and Pai in this issue.

The synergy of abiotic and biotic factors correlated with diversification of Fumarioideae (Papaveraceae) in the Cenozoic.

Rapid diversification of a group is often associated with exploiting an ecological opportunity and/or the evolution of a key innovation. However, how the interplay of such abiotic and biotic factors correlates with organismal diversification has been rarely documented in empirical studies, especially for organisms inhabiting drylands. Fumarioideae is the largest subfamily in Papaveraceae and is mainly distributed in temperate regions of the Northern Hemisphere. Here, we used one nuclear (ITS) and six plastid (rbcL, atpB, matK, rps16, trnL-F, and trnG) DNA sequences to investigate the spatio-temporal patterns of diversification and potential related factors of this subfamily. We first present the most comprehensive phylogenetic analysis of Fumarioideae to date. The results of our integrated molecular dating and biogeographic analyses indicate that the most recent common ancestor of Fumarioideae started to diversify in Asia during the Upper Cretaceous, and then dispersed multiple times out of Asia in the Cenozoic. In particular, we discover two independent dispersal events from Eurasia to East Africa in the late Miocene, suggesting that the Arabian Peninsula might be an important exchange corridor between Eurasia and East Africa in the late Miocene. Within the Fumarioideae, increased speciation rates were detected in two groups, Corydalis and Fumariinae. Corydalis first experienced a burst of diversification in its crown group at âˆ¼ 42 Ma, and further accelerated diversification from the mid-Miocene onwards. During these two periods, Corydalis had evolved diverse life history types, which could have facilitated the colonization of diverse habitats originating from extensive orogenesis in the Northern Hemisphere as well as Asian interior desertification. Fumariinae underwent a burst of diversification at âˆ¼ 15 Ma, which temporally coincides with the increasing aridification in central Eurasia, but is markedly posterior to the shifts in habitat (from moist to arid) and in life history (from perennial to annual) and to range expansion from Asia to Europe, suggesting that Fumariinae species may have been pre-adapted to invade European arid habitats by the acquisition of annual life history. Our study provides an empirical case that documents the importance of pre-adaptation on organismal diversification in drylands and highlights the significant roles of the synergy of abiotic and biotic factors in promoting plant diversification.

Differential susceptibility to parenting influences on reactive and proactive aggression: The role of testosterone and cortisol in children.

This study explored whether cortisol and testosterone moderate the effect of parenting style on children's aggressive behavior, in accordance with the diathesis-stress or differential susceptibility theory; i.e., whether children are vulnerable to negative parenting styles (diathesis-stress) or, in addition to this vulnerability, also benefit more from positive parenting (differential susceptibility). The sample group comprised 279 eight-year-old children (154 boys and 125 girls) from Spain. Aggressive behavior was assessed using the "Reactive and Proactive Questionnaire" (RPQ) and parenting styles were measured using the "Parenting Styles and Dimensions Questionnaire" (PSDQ). Additionally, three saliva samples were collected to measure testosterone and cortisol levels, which were analyzed using ELISA. The results revealed that girls' high testosterone levels moderated the association between mothers' authoritarian parenting style and reactive aggression. This result can be explained by the differential susceptibility model. None of the interactions were statistically significant in boys' proactive aggression. The study emphasizes the importance of investigating biological and social factors that may influence aggressive behavior.

Evolutionary history of the Arctic flora.

The Arctic tundra is a relatively young and new type of biome and is especially sensitive to the impacts of global warming. However, little is known about how the Arctic flora was shaped over time. Here we investigate the origin and evolutionary dynamics of the Arctic flora by sampling 32 angiosperm clades that together encompass 3626 species. We show that dispersal into the Arctic and in situ diversification within the Arctic have similar trends through time, initiating at approximately 10-9 Ma, increasing sharply around 2.6 Ma, and peaking around 1.0-0.7 Ma. Additionally, we discover the existence of a long-term dispersal corridor between the Arctic and western North America. Our results suggest that the initiation and diversification of the Arctic flora might have been jointly driven by progressive landscape and climate changes and sea-level fluctuations since the early Late Miocene. These findings have important conservation implications given rapidly changing climate conditions in the Arctic.

Comparative study of sex estimates in adult skulls using direct measurement and tomographic image reconstruction.

Sex estimation is an important procedure in forensic anthropology for human identification. The development of new technologies, such as three-dimensional computed tomography (CT), has provided excellent alternatives for this purpose. This study examined and compared a morphological method for sex estimation using two different approaches - direct measurement of physical structures and tomographic analysis using 3D images. A total of 111 skulls from the Museum of Human Anatomy at the University of São Paulo (MAH-USP) were used, (60 males and 51 females). All specimens were scanned by Philips Brilliance 64 CT scanner equipment and their corresponding images were reconstructed in three-dimensional (3D) models. The morphological characteristics of the skulls were analyzed by an observer who was blinded to the sex of the specimens. Five cranial structures were analyzed: external occipital crest, mastoid process, supraorbital margin, glabella, and mental eminence. The structures were scored 1 to 5 according to Buikstra and Ubelaker and validated by Walker. The success rates of the sex estimates obtained through direct measurement of the dry skulls ranged from 67.4% to 70.4% as compared to 60.2% to 68.1% for CT reconstruction. When analyzed separately, the maximum accuracy of the method was 68.33% in males and 88.24% in females in the physical analysis of structures. The glabella and mastoid process were the most effective structures to estimate sex through both techniques, respectively. Our results show that 3D CT images can be accurately used in the morphological analysis for sex estimation, representing a viable alternative in forensic anthropology.

Phylogeny and biogeography of Tiliacoreae (Menispermaceae), a tribe restricted to tropical rainforests.

BACKGROUND AND AIMS: Modern tropical rainforests house the highest biodiversity of Earth's terrestrial biomes and are distributed in three low-latitude areas. However, the biogeographical patterns and processes underlying the distribution of biodiversity among these three areas are still poorly known. Here, we used Tiliacoreae, a tribe of pantropical lianas with a high level of regional endemism, to provide new insights into the biogeographical relationships of tropical rainforests among different continents. METHODS: Based on seven plastid and two nuclear DNA regions, we reconstructed a phylogeny for Tiliacoreae with the most comprehensive sampling ever. Within the phylogenetic framework, we then estimated divergence times and investigated the spatiotemporal evolution of the tribe. KEY RESULTS: The monophyletic Tiliacoreae contain three major clades, which correspond to Neotropical, Afrotropical and Indo-Malesian/Australasian areas, respectively. Both Albertisia and Anisocycla are not monophyletic. The most recent common ancestor of Tiliacoreae occurred in Indo-Malesia, the Afrotropics and Neotropics in the early Eocene, then rapidly diverged into three major clades between 48 and 46 Ma. Three dispersals from Indo-Malesia to Australasia were inferred, one in the middle Eocene and two in the late Oligocene-late Miocene, and two dispersals from the Afrotropics to Indo-Malesia occurred in the late Eocene-Oligocene. CONCLUSIONS: The three main clades of Anisocycla correspond to three distinct genera [i.e. Anisocycla sensu stricto and two new genera (Georgesia and Macrophragma)]. Epinetrum is a member of Albertisia. Our findings highlight that sea-level fluctuations and climate changes in the Cenozoic have played important roles in shaping the current distribution and endemism of Tiliacoreae, hence contributing to the knowledge on the historical biogeography of tropical rainforests on a global scale.

Fathering and children's relational aggression: Moderating effects of children's temperament and gender.

In this exploratory study, we analyzed the contribution of fathering to relational aggression (RA) in middle childhood and the moderating role of children's temperament and gender. Participants (N = 234; 46% girls) were attending public elementary school (mean age = 8.15; SD = 1.23) in middle-class neighborhoods in two Spanish cities. Fathers provided information about their parenting practices using the Parenting Styles and Dimensions Questionnaire, parents gave data on their child's temperament using the Temperament in Middle Childhood Questionnaire and children provided information about their peers' aggressive behavior using the Mini Direct Indirect Aggression Inventory. Fathering dimensions considered were Authoritative Cold, Authoritative Warm, Physical Punishment, and Insecurity; temperament dimensions considered were negative affect (NA), effortful control (EC), activity (AC), and shyness (SH). Gender, fathering, and temperament dimensions additively accounted for a significant proportion of the variance observed in RA. Several significant interactions suggested that the effect of fathering on RA was moderated by temperament and, in some cases, by children's gender. NA increased the potential risk of Authoritative Cold fathering (CF) and, in boys only, of Insecure fathering, while EC potentiated the protective effect of Authoritative-Warm fathering and, in boys only, buffered the risk effect of CF. SH buffered the risk effect of CF and decreased the protective effect of Authoritative Warm fathering on RA. Lastly, AC also buffered the risk effect of CF on RA. Results are discussed in light of the protective or the vulnerability role of temperament and in relation to models that explain sensitivity differences to environmental contexts.

A complete genus-level phylogeny reveals the Cretaceous biogeographic diversification of the poppy family.

Angiosperms, a trigger for the Cretaceous Terrestrial Revolution (KTR), underwent a rapid expansion and occupied all the environments during the Mid-Upper Cretaceous. Yet, Cretaceous biogeographic patterns and processes underlying the distribution of angiosperm diversity in the Northern Hemisphere are still poorly known. Here, we elucidated the biogeographic diversification of the angiosperm family Papaveraceae, an ancient Northern Hemisphere clade characterized by poor dispersal ability and high level of regional endemism. Based on both plastome and multi-locus datasets, we reconstructed a robust time-calibrated phylogeny that includes all currently recognized 45 genera of this family. Within the time-calibrated phylogenetic framework, we conducted 72 biogeographic analyses by testing the sensitivity of uncertainties of area delimitation, maxarea constraints, and the parameters of the model, i.e., j (describing jump-dispersal events) and w (modifying dispersal multiplier matrices), to ancestral range estimations. We also inferred ancestral habitat and ecological niches. Phylogenetic analyses strongly support Papaveraceae as monophyletic. Pteridophylloideae is strongly supported as sister to Hypecoideae-Fumarioideae. Our results indicate that the j parameter and number of predefined areas strongly affect ancestral range estimates, generating questionable ancestral ranges, whereas maxarea constraint and w parameter have no effect and improve model fit. After accounting for these uncertainties, our results indicate that Papaveraceae differentiated in Asian wet forests during the Lower Cretaceous and subsequently occupied the Asian and western North American arid and open areas. Three dispersals from Asia to western North America via the Bering land bridge occurred in the Mid-Upper Cretaceous, largely in agreement with the KTR. Habitat shift and ecological niche divergence resulted in the subsequent disjunctions between Asia and western North America. These findings suggest that the interplay of range expansion and niche divergence-driven vicariance might have shaped Cretaceous biogeographic patterns of angiosperms with Papaveraceae-like ecological requirements and dispersal abilities in the Northern Hemisphere, hence contributing to the knowledge on the geographic expansion of angiosperms during the KTR.

The impact of quality control on cortical morphometry comparisons in autism.

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons, and a growing body of work has demonstrated the importance of careful quality control (QC) and evaluated the impact of image and image-processing quality. However, the growing size of typical neuroimaging datasets presents an additional challenge to QC, which is typically extremely time and labour intensive. One of the most important aspects of MRI quality is the accuracy of processed outputs, which have been shown to impact estimated neurodevelopmental trajectories. Here, we evaluate whether the quality of surface reconstructions by FreeSurfer (one of the most widely used MRI processing pipelines) interacts with clinical and demographic factors. We present a tool, FSQC, that enables quick and efficient yet thorough assessment of outputs of the FreeSurfer processing pipeline. We validate our method against other existing QC metrics, including the automated FreeSurfer Euler number, two other manual ratings of raw image quality, and two popular automated QC methods. We show strikingly similar spatial patterns in the relationship between each QC measure and cortical thickness; relationships for cortical volume and surface area are largely consistent across metrics, though with some notable differences. We next demonstrate that thresholding by QC score attenuates but does not eliminate the impact of quality on cortical estimates. Finally, we explore different ways of controlling for quality when examining differences between autistic individuals and neurotypical controls in the Autism Brain Imaging Data Exchange (ABIDE) dataset, demonstrating that inadequate control for quality can alter results of case-control comparisons.

Lichen planus of the esophagus: a case report.

Esophageal lichen planus (ELP) is an inflammatory disorder that affects the skin, cutaneous appendages and mucous membranes. The esophageal involvement is rare. We present the case of a 70-year-old woman with years of dysphagia and a history of erosive lichen planus involving the vulva, vagina, gingiva, and skin, who was eventually diagnosed with esophageal lichen planus. The patient's condition was refractory and progressed to the development of intraepithelial squamous neoplasia. We reviewed the literature on this condition.

Comparative study of sex estimates in adult skulls using direct measurement and tomographic image reconstruction

Abstract Sex estimation is an important procedure in forensic anthropology for human identification. The development of new technologies, such as three-dimensional computed tomography (CT), has provided excellent alternatives for this purpose. This study examined and compared a morphological method for sex estimation using two different approaches - direct measurement of physical structures and tomographic analysis using 3D images. A total of 111 skulls from the Museum of Human Anatomy at the University of São Paulo (MAH-USP) were used, (60 males and 51 females). All specimens were scanned by Philips Brilliance 64 CT scanner equipment and their corresponding images were reconstructed in three-dimensional (3D) models. The morphological characteristics of the skulls were analyzed by an observer who was blinded to the sex of the specimens. Five cranial structures were analyzed: external occipital crest, mastoid process, supraorbital margin, glabella, and mental eminence. The structures were scored 1 to 5 according to Buikstra and Ubelaker and validated by Walker. The success rates of the sex estimates obtained through direct measurement of the dry skulls ranged from 67.4% to 70.4% as compared to 60.2% to 68.1% for CT reconstruction. When analyzed separately, the maximum accuracy of the method was 68.33% in males and 88.24% in females in the physical analysis of structures. The glabella and mastoid process were the most effective structures to estimate sex through both techniques, respectively. Our results show that 3D CT images can be accurately used in the morphological analysis for sex estimation, representing a viable alternative in forensic anthropology.

Assembly dynamics of East Asian subtropical evergreen broadleaved forests: New insights from the dominant Fagaceae trees.

The dominant species of a biome can be regarded as its genuine indicator. Evergreen broadleaved forests (EBLFs) in subtropical East Asia harbor high levels of species biodiversity and endemism and are vital to regional carbon storage and cycling. However, the historical assembly of this unique biome is still controversial. Fagaceae is the most essential family in East Asian subtropical EBLFs and its dominant species are vital for the existence of this biome. Here, we used the dominant Fagaceae species to shed light on the dynamic process of East Asian subtropical EBLFs over time. Our results indicate high precipitation in summer and low temperature in winter are the most influential climatic factors for the distribution of East Asian subtropical EBLFs. Modern East Asian subtropical EBLFs did not begin to appear until 23 Ma, subsequently experienced a long-lasting development in the Miocene and markedly deteriorated at about 4 Ma, driven jointly by orogenesis and paleoclimate. We also document that there is a lag time between when one clade invaded the region and when its members become dominant species within the region. This study may improve our ability to predict and mitigate the threats to biodiversity of East Asian subtropical EBLFs and points to a new path for future studies involving multidisciplinary methods to explore the assembly of regional biomes.

Biotic colonization of subtropical East Asian caves through time.

Caves are home to unique and fragile biotas with high levels of endemism. However, little is known about how the biotic colonization of caves has developed over time, especially in caves from middle and low latitudes. Subtropical East Asia holds the world's largest karst landform with numerous ancient caves, which harbor a high diversity of cave-dwelling organisms and are regarded as a biodiversity hotspot. Here, we assess the temporal dynamics of biotic colonization of subtropical East Asian caves through a multi-taxon analysis with representatives of green plants, animals, and fungi. We then investigate the consequences of paleonviromental changes on the colonization dynamics of these caves in combination with reconstructions of vegetation, temperature, and precipitation. We discover that 88% of cave colonization events occurred after the Oligocene-Miocene boundary, and organisms from the surrounding forest were a major source for subtropical East Asian cave biodiversity. Biotic colonization of subtropical East Asian caves during the Neogene was subject to periods of acceleration and decrease, in conjunction with large-scale, seasonal climatic changes and evolution of local forests. This study highlights the long-term evolutionary interaction between surface and cave biotas; our climate-vegetation-relict model proposed for the subtropical East Asian cave biota may help explain the evolutionary origins of other mid-latitude subterranean biotas.

Infection order outweighs the role of CD4+ T cells in tertiary flavivirus exposure.

The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4+ depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.

Immigration dynamics of tropical and subtropical Southeast Asian limestone karst floras.

Ex situ origins and dispersal of taxa have played important roles in the assembly of island-like biodiversity hotspots. Insular limestone karsts in Southeast Asia are hotspots of biodiversity and endemism, but the immigration processes of their unique floras are still poorly known. Here, we used Gesneriaceae as a proxy to investigate the immigration dynamics of tropical and subtropical Southeast Asian karst floras. We present the most comprehensive phylogenetic analysis of the Old World gesneriads to date based on twelve loci. By estimating divergence times and reconstructing ancestral states (habitat, soil type and range), we found that immigration into subtropical Southeast Asian karst floras first occurred in the Early Miocene, with two peaks in the Early-Middle Miocene and the Pliocene-Early Pleistocene, whereas immigration into tropical Southeast Asian karsts initiated in the Late Eocene, with two peaks in the Late Oligocene and the Late Miocene. We also discover that Southeast Asian karst biodiversity comprises immigrant pre-adapted lineages and descendants from local acid soil ancestors, although niche shift from acid soil to karst in tropical Southeast Asian islands was lacking. This study advances our understanding of the historical assembly of Southeast Asian karst floras.

Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.

Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.

Biogeographic diversification of Eranthis (Ranunculaceae) reflects the geological history of the three great Asian plateaus.

The evolutionary history of organisms with poor dispersal abilities usually parallels geological events. Collisions of the Indian and Arabian plates with Eurasia greatly changed Asian topography and affected regional and global climates as well as biotic evolution. However, the geological evolution of Asia related to these two collisions remains debated. Here, we used Eranthis, an angiosperm genus with poor seed dispersal ability and a discontinuous distribution across Eurasia, to shed light on the orogenesis of the Qinghai-Tibetan, Iranian and Mongolian Plateaus. Our phylogenetic analyses show that Eranthis comprises four major geographical clades: east Qinghai-Tibetan Plateau clade (I-1), North Asian clade (I-2), west Qinghai-Tibetan Plateau clade (II-1) and Mediterranean clade (II-2). Our molecular dating and biogeographic analyses indicate that within Eranthis, four vicariance events correlate well with the two early uplifts of the Qinghai-Tibetan Plateau during the Late Eocene and the Oligocene-Miocene boundary and the two uplifts of the Iranian Plateau during the Middle and Late Miocene. The origin and divergence of the Mongolian Plateau taxa are related to the two uplifts of the Mongolian Plateau during the Middle and Late Miocene. Additionally, our results are in agreement with the hypothesis that the central part of Tibet only reached an altitude of less than 2.3 km at approximately 40 Ma. This study highlights that organismal evolution could be related to the formation of the three great Asian plateaus, hence contributing to the knowledge on the timing of the key tectonic events in Asia.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.