Shared Genetic Variation Research Articles

The Evolving Epidemiology of Nasopharyngeal Carcinoma.

The epidemiology of nasopharyngeal carcinoma (NPC) has long been a source of fascination due to the malignancy's striking geographic distribution, the involvement of the oncogenic Epstein-Barr virus (EBV), the unique association with intake of Chinese-style salt-preserved fish, and etiologic heterogeneity by histologic subtype. This review summarizes the current epidemiologic literature on NPC, highlighting recent results from our population-based case-control study in southern China. Findings from our case-control study provide new insight into the epidemiology of NPC, including a diminished role of Chinese-style salt-preserved fish, a profound impact of EBV genetic sequence variation, modest positive associations with passive smoking and household air pollution, and possible effects of oral health and the oral microbiome. Recent findings from other studies include a protective association with infectious mononucleosis, suggesting a causal role of early EBV infection; familial risk conferred by shared genetic variation in the host antibody-mediated immune response to EBV infection; and an unclear association with occupational exposure to formaldehyde. To shed further light on the interplay of environmental, genetic, and viral causes of NPC, large pooled studies must accumulate sufficient cases with detailed exposure data. New epidemiologic findings have reshaped the causal model for NPC.

Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: a GWAS meta-analysis

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10–8) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10–4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10–4) and in the cross-disorder meta-analysis (p < 5 × 10–8). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.

Incomplete lineage sorting and ancient admixture, and speciation without morphological change in ghost-worm cryptic species.

Morphologically similar species, that is cryptic species, may be similar or quasi-similar owing to the deceleration of morphological evolution and stasis. While the factors underlying the deceleration of morphological evolution or stasis in cryptic species remain unknown, decades of research in the field of paleontology on punctuated equilibrium have originated clear hypotheses. Species are expected to remain morphologically identical in scenarios of shared genetic variation, such as hybridization and incomplete lineage sorting, or in scenarios where bottlenecks reduce genetic variation and constrain the evolution of morphology. Here, focusing on three morphologically similar Stygocapitella species, we employ a whole-genome amplification method (WGA) coupled with double-digestion restriction-site associated DNA sequencing (ddRAD) to reconstruct the evolutionary history of the species complex. We explore population structure, use population-level statistics to determine the degree of connectivity between populations and species, and determine the most likely demographic scenarios which generally reject for recent hybridization. We find that the combination of WGA and ddRAD allowed us to obtain genomic-level data from microscopic eukaryotes (∼1 millimetre) opening up opportunities for those working with population genomics and phylogenomics in such taxa. The three species share genetic variance, likely from incomplete lineage sorting and ancient admixture. We speculate that the degree of shared variation might underlie morphological similarity in the Atlantic species complex.

Family History Extraction From Synthetic Clinical Narratives Using Natural Language Processing: Overview and Evaluation of a Challenge Data Set and Solutions for the 2019 National NLP Clinical Challenges (n2c2)/Open Health Natural Language Processing (OHNLP) Competition.

BackgroundAs a risk factor for many diseases, family history (FH) captures both shared genetic variations and living environments among family members. Though there are several systems focusing on FH extraction using natural language processing (NLP) techniques, the evaluation protocol of such systems has not been standardized.ObjectiveThe n2c2/OHNLP (National NLP Clinical Challenges/Open Health Natural Language Processing) 2019 FH extraction task aims to encourage the community efforts on a standard evaluation and system development on FH extraction from synthetic clinical narratives.MethodsWe organized the first BioCreative/OHNLP FH extraction shared task in 2018. We continued the shared task in 2019 in collaboration with the n2c2 and OHNLP consortium, and organized the 2019 n2c2/OHNLP FH extraction track. The shared task comprises 2 subtasks. Subtask 1 focuses on identifying family member entities and clinical observations (diseases), and subtask 2 expects the association of the living status, side of the family, and clinical observations with family members to be extracted. Subtask 2 is an end-to-end task which is based on the result of subtask 1. We manually curated the first deidentified clinical narrative from FH sections of clinical notes at Mayo Clinic Rochester, the content of which is highly relevant to patients’ FH.ResultsA total of 17 teams from all over the world participated in the n2c2/OHNLP FH extraction shared task, where 38 runs were submitted for subtask 1 and 21 runs were submitted for subtask 2. For subtask 1, the top 3 runs were generated by Harbin Institute of Technology, ezDI, Inc., and The Medical University of South Carolina with F1 scores of 0.8745, 0.8225, and 0.8130, respectively. For subtask 2, the top 3 runs were from Harbin Institute of Technology, ezDI, Inc., and University of Florida with F1 scores of 0.681, 0.6586, and 0.6544, respectively. The workshop was held in conjunction with the AMIA 2019 Fall Symposium.ConclusionsA wide variety of methods were used by different teams in both tasks, such as Bidirectional Encoder Representations from Transformers, convolutional neural network, bidirectional long short-term memory, conditional random field, support vector machine, and rule-based strategies. System performances show that relation extraction from FH is a more challenging task when compared to entity identification task.

The Legacy of Recurrent Introgression during the Radiation of Hares.

Hybridization may often be an important source of adaptive variation, but the extent and long-term impacts of introgression have seldom been evaluated in the phylogenetic context of a radiation. Hares (Lepus) represent a widespread mammalian radiation of 32 extant species characterized by striking ecological adaptations and recurrent admixture. To understand the relevance of introgressive hybridization during the diversification of Lepus, we analyzed whole exome sequences (61.7 Mb) from 15 species of hares (1–4 individuals per species), spanning the global distribution of the genus, and two outgroups. We used a coalescent framework to infer species relationships and divergence times, despite extensive genealogical discordance. We found high levels of allele sharing among species and show that this reflects extensive incomplete lineage sorting and temporally layered hybridization. Our results revealed recurrent introgression at all stages along the Lepus radiation, including recent gene flow between extant species since the last glacial maximum but also pervasive ancient introgression occurring since near the origin of the hare lineages. We show that ancient hybridization between northern hemisphere species has resulted in shared variation of potential adaptive relevance to highly seasonal environments, including genes involved in circadian rhythm regulation, pigmentation, and thermoregulation. Our results illustrate how the genetic legacy of ancestral hybridization may persist across a radiation, leaving a long-lasting signature of shared genetic variation that may contribute to adaptation. [Adaptation; ancient introgression; hybridization; Lepus; phylogenomics.]

Common mechanisms for type 2 diabetes and psychosis: Findings from a prospective birth cohort

BackgroundPsychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation. MethodsPsychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses. ResultsGenetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01–1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04–2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99–1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p = .040). ConclusionsComorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.

Parallelism in eco-morphology and gene expression despite variable evolutionary and genomic backgrounds in a Holarctic fish.

Understanding the extent to which ecological divergence is repeatable is essential for predicting responses of biodiversity to environmental change. Here we test the predictability of evolution, from genotype to phenotype, by studying parallel evolution in a salmonid fish, Arctic charr (Salvelinus alpinus), across eleven replicate sympatric ecotype pairs (benthivorous-planktivorous and planktivorous-piscivorous) and two evolutionary lineages. We found considerable variability in eco-morphological divergence, with several traits related to foraging (eye diameter, pectoral fin length) being highly parallel even across lineages. This suggests repeated and predictable adaptation to environment. Consistent with ancestral genetic variation, hundreds of loci were associated with ecotype divergence within lineages of which eight were shared across lineages. This shared genetic variation was maintained despite variation in evolutionary histories, ranging from postglacial divergence in sympatry (ca. 10-15kya) to pre-glacial divergence (ca. 20-40kya) with postglacial secondary contact. Transcriptome-wide gene expression (44,102 genes) was highly parallel across replicates, involved biological processes characteristic of ecotype morphology and physiology, and revealed parallelism at the level of regulatory networks. This expression divergence was not only plastic but in part genetically controlled by parallel cis-eQTL. Lastly, we found that the magnitude of phenotypic divergence was largely correlated with the genetic differentiation and gene expression divergence. In contrast, the direction of phenotypic change was mostly determined by the interplay of adaptive genetic variation, gene expression, and ecosystem size. Ecosystem size further explained variation in putatively adaptive, ecotype-associated genomic patterns within and across lineages, highlighting the role of environmental variation and stochasticity in parallel evolution. Together, our findings demonstrate the parallel evolution of eco-morphology and gene expression within and across evolutionary lineages, which is controlled by the interplay of environmental stochasticity and evolutionary contingencies, largely overcoming variable evolutionary histories and genomic backgrounds.

Genetic diversity among cultivated beets (Beta vulgaris) assessed via population-based whole genome sequences

BackgroundDiversification on the basis of utilization is a hallmark of Beta vulgaris (beet), as well as other crop species. Often, crop improvement and management activities are segregated by crop type, thus preserving unique genome diversity and organization. Full interfertility is typically retained in crosses between these groups and more traits may be accessible if the genetic basis of crop type lineage were known, along with available genetic markers to effect efficient transfer (e.g., via backcrossing). Beta vulgaris L. (2n =18) is a species complex composed of diverged lineages (e.g., crop types), including the familiar table, leaf (chard), fodder, and sugar beet crop types. Using population genetic and statistical methods with whole genome sequence data from pooled samples of 23 beet cultivars and breeding lines, relationships were determined between accessions based on identity-by-state metrics and shared genetic variation among lineages.ResultsDistribution of genetic variation within and between crop types showed extensive shared (e.g. non-unique) genetic variation. Lineage specific variation (e.g. apomorphy) within crop types supported a shared demographic history within each crop type, while principal components analysis revealed strong crop type differentiation. Relative contributions of specific chromosomes to genome wide differentiation were ascertained, with each chromosome revealing a different pattern of differentiation with respect to crop type. Inferred population size history for each crop type helped integrate selection history for each lineage, and highlighted potential genetic bottlenecks in the development of cultivated beet lineages.ConclusionsA complex evolutionary history of cultigroups in Beta vulgaris was demonstrated, involving lineage divergence as a result of selection and reproductive isolation. Clear delineation of crop types was obfuscated by historical gene flow and common ancestry (e.g. admixture and introgression, and sorting of ancestral polymorphism) which served to share genome variation between crop types and, likely, important phenotypic characters. Table beet was well differentiated as a crop type, and shared more genetic variation within than among crop types. The sugar beet group was not quite as well differentiated as the table beet group. Fodder and chard groups were intermediate between table and sugar groups, perhaps the result of less intensive selection for end use.

Effects of Genetic Variants on Stroke Risk.

Effects of Genetic Variants on Stroke Risk.

AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design

The CRISPR/Cas system is a highly specific genome editing tool capable of distinguishing alleles differing by even a single base pair. Target sites might carry genetic variations that are not distinguishable by sgRNA designing tools based on one reference genome. AlleleAnalyzer is an open-source software that incorporates single-nucleotide variants and short insertions and deletions to design sgRNAs for precisely editing 1 or multiple haplotypes of a sequenced genome, currently supporting 11 Cas proteins. It also leverages patterns of shared genetic variation to optimize sgRNA design for different human populations. AlleleAnalyzer is available at https://github.com/keoughkath/AlleleAnalyzer.

Inheritance of Neural Substrates for Motivation and Pleasure

Despite advances in the understanding of the reward system and the role of dopamine in recent decades, the heritability of the underlying neural mechanisms is not known. In the present study, we examined the hemodynamic activation of the nucleus accumbens (NAcc), a key hub of the reward system, in 86 healthy monozygotic twins and 88 healthy dizygotic twins during a monetary-incentive-delay task. The participants also completed self-report measures of pleasure. Using voxelwise heritability mapping, we found that activation of the bilateral NAcc during the anticipation of monetary gains had significant heritability (h2 = .20–.49). Moreover, significant shared genetic covariance was observed between pleasure and NAcc activation during the anticipation of monetary gain. These findings suggest that both NAcc activation and self-reported pleasure may be heritable and that their phenotypic correlation may be partially explained by shared genetic variation.

DOZ047.32: Infantile hypertrophic pyloric stenosis in patients with esophageal atresia: proposal for a causative seesaw model

Abstract Aim of the Study Patients born with esophageal atresia (EA) appear to have a 30 times higher prevalence of infantile hypertrophic pyloric stenosis (IHPS). This makes sense from a developmental perspective as both the esophagus and the pyloric sphincter are foregut derived structures. We hypothesized that genetic defects, disturbing foregut morphogenesis, are responsible for the specific combination of EA and IHPS. Methods Patients with both EA and IHPS born between 1970 and 2017 and where possible their parents were included. This study was approved by the internal review board of the Erasmus MC. After parental written informed consent, we determined genetic profiles with whole exome sequencing and SNP-array-based copy number variation analysis. We focused on (1) genetic variation in known EA and IHPS disease genes, (2) pathways important for foregut morphogenesis, (3) shared rare genetic variation, and (4) ultrarare variants in variant-intolerant genes, which have a high chance of being de novo. Segregation analysis of possible candidate variants was performed. Results Twenty-seven out of 664 patients (4.1%) born with EA during the study period developed IHPS, of which 15 cases were analyzed. As none of the parents were affected, we considered dominant (de novo) or recessive and X-linked inheritance models. Unfortunately, we could neither identify rare de novo mutations, nor variants fitting a recessive model. We did however identify inherited putative deleterious heterozygous variants in genes either known to be involved in EA or IHPS (e.g., COL7A1, TNXB, WDR11, GDF6) or important in foregut morphogenesis (e.g., GLI3, NKX2.1) in all patients. Moreover, seven genes were affected by rare variation in ≥2 patients (ADAMTSL4, ANKRD26, CNTN2, HSPG2, KCNN3, LDB3, SEC16B) and expressed in the developing foregut, esophagus or pyloric sphincter in mice between E8.25 and E18.5. However, burden analysis did not show a significant difference with unaffected controls. Conclusions Although the presence of genetic variation in likely candidate genes suggests a genetic component, genetic factors alone could not explain the abnormalities seen in these patients. Therefore, we propose a multifactorial model in which the combination of high impact genetic, mechanical, and environmental factors together can shift the balance from normal to abnormal development.

Phylogenomics of an extra-Antarctic notothenioid radiation reveals a previously unrecognized lineage and diffuse species boundaries

BackgroundThe impressive adaptive radiation of notothenioid fishes in Antarctic waters is generally thought to have been facilitated by an evolutionary key innovation, antifreeze glycoproteins, permitting the rapid evolution of more than 120 species subsequent to the Antarctic glaciation. By way of contrast, the second-most species-rich notothenioid genus, Patagonotothen, which is nested within the Antarctic clade of Notothenioidei, is almost exclusively found in the non-Antarctic waters of Patagonia. While the drivers of the diversification of Patagonotothen are currently unknown, they are unlikely to be related to antifreeze glycoproteins, given that water temperatures in Patagonia are well above freezing point. Here we performed a phylogenetic analysis based on genome-wide single nucleotide polymorphisms (SNPs) derived from restriction site-associated DNA sequencing (RADseq) in a total of twelve Patagonotothen species.ResultsWe present a well-supported, time-calibrated phylogenetic hypothesis including closely and distantly related outgroups, confirming the monophyly of the genus Patagonotothen with an origin approximately 3 million years ago and the paraphyly of both the sister genus Lepidonotothen and the family Notothenidae. Our phylogenomic and population genetic analyses highlight a previously unrecognized linage and provide evidence for shared genetic variation between some closely related species. We also provide a mitochondrial phylogeny showing mitonuclear discordance.ConclusionsBased on a combination of phylogenomic and population genomic approaches, we provide evidence for the existence of a new, potentially cryptic, Patagonotothen species, and demonstrate that genetic boundaries between some closely related species are diffuse, likely due to recent introgression and/or incomplete linage sorting. The detected mitonuclear discordance highlights the limitations of relying on a single locus for species barcoding. In addition, our time-calibrated phylogenetic hypothesis shows that the early burst of diversification roughly coincides with the onset of the intensification of Quaternary glacial cycles and that the rate of species accumulation may have been stepwise rather than constant. Our phylogenetic framework not only advances our understanding of the origin of a high-latitude marine radiation, but also provides the basis for the study of the ecology and life history of the genus Patagonotothen, as well as for their conservation and commercial management.

Persistence of psychosis in the population: Τhe cost and the price for humanity

Schizophrenia is a chronic and highly impairing condition that affects around 1% of the human population. Evolutionary theories lend support for the idea of a continuum approach to the diagnosis of psychosis. Subclinical psychotic-like experiences are relatively common in children and adolescents, occurring in about 17% of youths. The prevalence rate of psychotic symptoms in the general population is up to 8%, which is about ten times higher than the prevalence of diagnosed psychotic disorders. Some scientists have argued that there may be a shared genetic variation between illness and non-clinical psychotic- like symptom expression. The high prevalence of non-clinical psychotic symptoms in the population prompt neuroscientists to re-evaluate these symptoms in the light of evolutionary theory. The schizophrenia impaired physical health and reduced probability of reproduction raises an evolutionary puzzle. How does schizophrenia persist in the population at a stable prevalence rate? The question regarding what processes maintain the persistence of high heritable variation in relatively disadvantageous traits, such as schizotypy, in the general population, remains a universal challenge across the domains of psychiatric and evolutionary genetics. Furthermore, is there any link between the evolutionary persistence of psychosis in the population worldwide and the association of creativity with psychoticlike experiences in the general population? There has been a healthy debate on many hypotheses. One possibility is that schizophrenia remains in the human population because of shared genetic linkages to creativity. During last decade many scientists search the explanation for the evolutionary enigma of the persistence of schizophrenia, and the nature of its relation to creativity, although the notion that there is a heritable aspect of at least some aspects of high ability, including creativity, is going back at least to Francis Galton's book Hereditary genius (1869). Neuroscientists also suggested that schizophrenia may emerge as a by-product of social cognition or that certain types of hallucinations could be viewed as evolutionary by-products of a cognitive system designed to detect threat. Some traits, such as schizotypy, may have an optimal level of expression that is advantageous within the community. However, this trait has adverse consequences for the psychotic person, which becomes, as Sebastian Faulks (2006) suggested, "the price we pay for being what we are".

SU23 - ASSOCIATIONS OF POLYGENIC RISK OF SCHIZOPHRENIA AND MAJOR DEPRESSION IN STUDIES OF BIPOLAR DISORDER AND MAJOR DEPRESSION

Background Large Genome-Wide Association Studies (GWAS) have identified common genetic variants that underlie Schizophrenia (SCZ) and Major Depressive Disorder (MDD), although Bipolar Disorder (BD) remains elusive. Cross disorder analysis has shown a strong genetic correlation of SCZ with BD, with modest correlations of SCZ with MDD, and MDD with BD. We used polygenic risk scores to examine shared genetic variation among disorders and to dissect the genetic contribution to shared clinical features, such as psychotic symptoms. Methods Participants from the Kaiser Permanente Research Program on Genes, Environment, and Health (9,080 MDD cases; 54,808 controls) and a multi-ethnic GWAS of bipolar 1 disorder (BD1) (5,056 cases; 54,808 controls) were genotyped on the Affymetrix Axiom system, using ancestry-specific arrays, and the data imputed to the 1000 Genome Project (March 2012 release). We calculated standardized polygenic risk scores for SCZ (SCZ-GRS) and MDD (MDD-GRS) as the weighted sum of risk alleles using 128 SNPs and 47 SNPs that were significantly associated with SCZ and MDD, respectively, in independent GWAS. Two SNPs were common to both scores. Logistic regression analyses of the association of SCZ-GRS and MDD-GRS with BD1 and MDD, separately, included gender, age, and principal components for adjustment of ancestry. Analyses were conducted separately in race-ethnicity groups and by gender. Results The SCZ-GRS and MDD-GRS were significantly and independently associated with BD1 in non-Hispanic whites (3,725 cases, 52,430 controls) in an analysis including both (Odds Ratio (OR)-MDD-GRS=1.138; 95% CI=1.099, 1.178; p= 2.646×10–13; OR-SCZ-GRS=1.146 95% CI=1.107, 1.187; p= 1.241×10–14), with similar results in the smaller samples of minorities, and in men and women. There was no interaction between the scores. Among BD1 cases, the SCZ-GRS was significantly associated with psychotic symptoms and hospitalization for BD; the MDD-GRS was also modestly associated with psychotic symptoms and nominally with rapid cycling of moods, a hallmark of BD. In analyses of MDD in non-Hispanic whites (7,833 cases; 43,581 controls), the MDD-GRS was significantly associated with MDD (OR=1.147; 95% CI=1.119,1.176; p=3.13×10–27), but the SCZ-GRS was not (OR=1.017; 95% CI=0.992, 1.042; p=0.189). Similar results were found in race-ethnic minorities, and in men and women. There was no interaction. Neither the MDD-GRS nor the SCZ-GRS was associated with hospitalization or psychotic symptoms in MDD, although the prevalence was much lower in MDD than BD. Discussion BD has both cognitive and affective components, most often including depressive episodes like those in MDD, but also frequently including psychotic symptoms, as does SCZ. The independent association of the MDD-GRS and SCZ-GRS with BD1 suggests that different genetic variants may contribute to the cognitive and affective clinical features of BD. In this study, genetic variation associated with SCZ was not associated with MDD, or with psychotic symptoms in MDD. Identification of genetic variation that influences specific disorders and specific features of disorders increases knowledge about the genetic etiology of disorders and may contribute to understanding the underlying biology of disorders and identification of new targets for treatment.

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Short-acting β2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69×10−9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5×10−8). Our results failed to replicate in three additional populations of 416 Latinos and 1,615 African Americans. Our findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

Characterization of the contribution of shared environmental and genetic factors to metabolic syndrome methylation heritability and familial correlations

BackgroundTransgenerational epigenetic inheritance has been posited as a possible contributor to the observed heritability of metabolic syndrome (MetS). Yet the extent to which estimates of epigenetic inheritance for DNA methylation sites are inflated by environmental and genetic covariance within families is still unclear. We applied current methods to quantify the environmental and genetic contributors to the observed heritability and familial correlations of four previously associated MetS methylation sites at three genes (CPT1A, SOCS3 and ABCG1) using real data made available through the GAW20.ResultsOur findings support the role of both shared environment and genetic variation in explaining the heritability of MetS and the four MetS cytosine-phosphate-guanine (CpG) sites, although the resulting heritability estimates were indistinguishable from one another. Familial correlations by type of relative pair generally followed our expectation based on relatedness, but in the case of sister and parent pairs we observed nonsignificant trends toward greater correlation than expected, as would be consistent with the role of shared environmental factors in the inflation of our estimated correlations.ConclusionsOur work provides an interesting and flexible statistical framework for testing models of epigenetic inheritance in the context of human family studies. Future work should endeavor to replicate our findings and advance these methods to more robustly describe epigenetic inheritance patterns in human populations.

Domestication of cattle: Two or three events?

Cattle have been invaluable for the transition of human society from nomadic hunter‐gatherers to sedentary farming communities throughout much of Europe, Asia and Africa since the earliest domestication of cattle more than 10,000 years ago. Although current understanding of relationships among ancestral populations remains limited, domestication of cattle is thought to have occurred on two or three occasions, giving rise to the taurine (Bos taurus) and indicine (Bos indicus) species that share the aurochs (Bos primigenius) as common ancestor ~250,000 years ago. Indicine and taurine cattle were domesticated in the Indus Valley and Fertile Crescent, respectively; however, an additional domestication event for taurine in the Western Desert of Egypt has also been proposed. We analysed medium density Illumina Bovine SNP array (~54,000 loci) data across 3,196 individuals, representing 180 taurine and indicine populations to investigate population structure within and between populations, and domestication and demographic dynamics using approximate Bayesian computation (ABC). Comparative analyses between scenarios modelling two and three domestication events consistently favour a model with only two episodes and suggest that the additional genetic variation component usually detected in African taurine cattle may be explained by hybridization with local aurochs in Africa after the domestication of taurine cattle in the Fertile Crescent. African indicine cattle exhibit high levels of shared genetic variation with Asian indicine cattle due to their recent divergence and with African taurine cattle through relatively recent gene flow. Scenarios with unidirectional or bidirectional migratory events between European taurine and Asian indicine cattle are also plausible, although further studies are needed to disentangle the complex human‐mediated dispersion patterns of domestic cattle. This study therefore helps to clarify the effect of past demographic history on the genetic variation of modern cattle, providing a basis for further analyses exploring alternative migratory routes for early domestic populations.

Abstract 5383: Tumor evolution of uterine leiomyosarcoma from a benign leiomyoma precursor

Abstract Uterine leiomyosarcoma (ULMS) is a highly aggressive smooth muscle tumor with poorly understood pathogenesis. Although ULMS is believed to develop as a de novo tumor, it has been suggested that in some cases uterine leiomyoma (UL) could serve as a precursor lesion for the pathogenesis. ULs are extremely common tumors affecting up to 70% of women. Whereas 90% of ULs are classified as conventional ULs, 10% of the tumors represent subtype histopathologies, some of which have features associated with malignancy. These subtypes include tumors with bizarre nuclei and increased cellularity. In this study, we investigated the genetic and molecular background of one ULMS showing simultaneously mixed histopathologies of UL with bizarre nuclei and cellular UL. The study material consisted of four formalin-fixed paraffin-embedded samples having distinct areas of ULMS, UL with bizarre nuclei, and cellular UL. Fallopian tube sample was used as a normal control. Libraries for exome sequencing were prepared with KAPA Library Preparation Kit and subjected to exome capture with NimbleGen SeqCap EZ System (Roche). Paired-end sequencing was performed with HiSeq2500 (Illumina). SNP genotyping data was produced with Infinium Omni2.5-8 Kit (Illumina). Immunohistochemistry was performed to proteins commonly displaying aberrant expression in UL and/or ULMS. Telomere-specific fluorescence in situ hybridization was conducted to detect alternatively lengthened telomeres (ALT), a feature often associated with ULMS pathogenesis. Exome sequencing data and protein expression analyses revealed that all tumor compartments were negative for UL driver alterations, including MED12 mutations, HMGA2 overexpression and biallelic FH inactivation. Data from exome sequencing indicated that ULMS shared the largest number of variants with UL with bizarre nuclei, including the pathogenic splice site mutation c.994-1G&amp;gt;A in tumor protein 53 (TP53). SNP genotyping data showed identical and large chromosomal aberrations in 6q, 9p, 10q and 19q in ULMS and UL with bizarre nuclei. No such aberrations were shared between ULMS and cellular UL. All tumor compartments shared changes in chromosomes 1q, 2p, 12q, 13q, 17q and 17p. ULMS showed prominent ALT, whereas UL with bizarre nuclei had a weaker ALT phenotype. Cellular UL had normal telomere lengths. In conclusion, these results suggest that the genome, including telomeres, of UL with bizarre nuclei resembles that of ULMS. Large genomic events have probably occurred in UL with bizarre nuclei during tumor evolution, leading to unstable chromosomes, which in turn favored the development of ULMS. Also, all tumor compartments displayed shared genetic variation, suggesting a common evolutionary origin. Understanding the pathogenesis of ULMS and the malignant potential of ULs is clinically highly relevant, as it may improve the diagnosis, prevent malignant transformation and enable the design of new treatments. Citation Format: Netta Mäkinen, Terhi Ahvenainen, Pernilla von Nandelstadh, Ralf Bützow, Pia Vahteristo. Tumor evolution of uterine leiomyosarcoma from a benign leiomyoma precursor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5383.

Neutral and functionally important genes shed light on phylogeography and the history of high-altitude colonization in a widespread New World duck.

Phylogeographic studies often infer historical demographic processes underlying species distributions based on patterns of neutral genetic variation, but spatial variation in functionally important genes can provide additional insights about biogeographic history allowing for inferences about the potential role of adaptation in geographic range evolution. Integrating data from neutral markers and genes involved in oxygen (O2)‐transport physiology, we test historical hypotheses about colonization and gene flow across low‐ and high‐altitude regions in the Ruddy Duck (Oxyura jamaicensis), a widely distributed species in the New World. Using multilocus analyses that for the first time include populations from the Colombian Andes, we also examined the hypothesis that Ruddy Duck populations from northern South America are of hybrid origin. We found that neutral and functional genes appear to have moved into the Colombian Andes from both North America and southern South America, and that high‐altitude Colombian populations do not exhibit evidence of adaptation to hypoxia in hemoglobin genes. Therefore, the biogeographic history of Ruddy Ducks is likely more complex than previously inferred. Our new data raise questions about the hypothesis that adaptation via natural selection to high‐altitude conditions through amino acid replacements in the hemoglobin protein allowed Ruddy Ducks to disperse south along the high Andes into southern South America. The existence of shared genetic variation with populations from both North America and southern South America as well as private alleles suggests that the Colombian population of Ruddy Ducks may be of old hybrid origin. This study illustrates the breadth of inferences one can make by combining data from nuclear and functionally important loci in phylogeography, and underscores the importance of complete range‐wide sampling to study species history in complex landscapes.