Potential Genetic Basis Research Articles

An Automated Method To Predict Mouse Gene and Protein Sequences Using Variant Data.

With recent advances in sequencing technologies, the scientific community has begun to probe the potential genetic bases behind complex phenotypes in humans and model organisms. In many cases, the genomes of genetically distinct strains of model organisms, such as the mouse (Mus musculus), have not been fully sequenced. Here, we report on a tool designed to use single-nucleotide polymorphism (SNP) and insertion-deletion (indel) data to predict gene, mRNA, and protein sequences for up to 36 genetically distinct mouse strains. By automated querying of freely accessible databases through a graphical interface, the software requires no data and little computational experience. As a proof of concept, we predicted the gene and amino acid sequence of the aryl hydrocarbon receptor (Ahr) for all inbred mouse strains of which variant data were currently available through Mouse Genome Project. Predicted sequences were compared with fully sequenced genomes to show that the tool is effective in predicting gene and protein sequences.

Parallel and nonparallel genomic responses contribute to herbicide resistance in Ipomoea purpurea, a common agricultural weed.

The repeated evolution of herbicide resistance has been cited as an example of genetic parallelism, wherein separate species or genetic lineages utilize the same genetic solution in response to selection. However, most studies that investigate the genetic basis of herbicide resistance examine the potential for changes in the protein targeted by the herbicide rather than considering genome-wide changes. We used a population genomics screen and targeted exome re-sequencing to uncover the potential genetic basis of glyphosate resistance in the common morning glory, Ipomoea purpurea, and to determine if genetic parallelism underlies the repeated evolution of resistance across replicate resistant populations. We found no evidence for changes in 5‐enolpyruvylshikimate‐3‐phosphate synthase (EPSPS), glyphosate’s target protein, that were associated with resistance, and instead identified five genomic regions that showed evidence of selection. Within these regions, genes involved in herbicide detoxification—cytochrome P450s, ABC transporters, and glycosyltransferases—are enriched and exhibit signs of selective sweeps. One region under selection shows parallel changes across all assayed resistant populations whereas other regions exhibit signs of divergence. Thus, while it appears that the physiological mechanism of resistance in this species is likely the same among resistant populations, we find patterns of both similar and divergent selection across separate resistant populations at particular loci.

Genetic Paths to Evolutionary Rescue and the Distribution of Fitness Effects Along Them.

The past century has seen substantial theoretical and empirical progress on the genetic basis of adaptation. Over this same period, a pressing need to prevent the evolution of drug resistance has uncovered much about the potential genetic basis of persistence in declining populations. However, we have little theory to predict and generalize how persistence-by sufficiently rapid adaptation-might be realized in this explicitly demographic scenario. Here, we use Fisher's geometric model with absolute fitness to begin a line of theoretical inquiry into the genetic basis of evolutionary rescue, focusing here on asexual populations that adapt through de novo mutations. We show how the dominant genetic path to rescue switches from a single mutation to multiple as mutation rates and the severity of the environmental change increase. In multi-step rescue, intermediate genotypes that themselves go extinct provide a "springboard" to rescue genotypes. Comparing to a scenario where persistence is assured, our approach allows us to quantify how a race between evolution and extinction leads to a genetic basis of adaptation that is composed of fewer loci of larger effect. We hope this work brings awareness to the impact of demography on the genetic basis of adaptation.

Genomic evidence of population genetic differentiation in deep-sea squat lobster Shinkaia crosnieri (crustacea: Decapoda: Anomura) from Northwestern Pacific hydrothermal vent and cold seep

The galatheid squat lobster, Shinkaia crosnieri Baba and Williams, 1998, is one of the few dominant species inhabiting both deep-sea hydrothermal vents and cold seeps. Here, we used mitochondrial cytochrome c oxidase subunit I (mtDNA COI) and nuclear genome-wide single nucleotide polymorphism (SNP) as genetic markers to investigate genetic connectivity of S. crosnieri populations from a hydrothermal vent of Okinawa Through and a cold seep of the South China Sea. MtDNA COI sequence analyses indicated that deep-sea vent population of S. crosnieri was genetically divergent from cold seep population. To obtain deep insights into the evolutionary forces driving this genetic break, we performed restriction-site associated DNA analysis to evaluate the extent of genetic differentiation in S. crosnieri inhabiting both environments on a genome-wide scale, and to assess the role of selective processes in shaping this pattern. Using the assembled survey genome of S. crosnieri as a reference, 12,963 SNPs were identified for 30 S. crosnieri specimens. The structural and principle component analyses based on SNPs supported genetic differentiation between the vent and seep populations. Evidence for local adaptation of S. crosnieri populations was confirmed by identifying increased population divergence using FST-based outlier tests, which resulted in 54 potentially locally selected SNPs, indicative of an important role for natural selection as a driver of genetic divergence in this species. Further studies revealed that candidate genes containing outlier SNPs were involved in diverse biological processes, including immunity, transposon and metabolic processes. Overall, our results demonstrated significant genetic divergence between the vent and seep S. crosnieri populations in the Northwestern Pacific and provided clues to understand potential genetic basis underlying local adaptation in S. crosnieri during colonization into deep-sea chemosynthetic ecosystems.

A comparative synthesis of transcriptomic analyses reveals major differences between WSSV-susceptible Litopenaeus vannamei and WSSV-refractory Macrobrachium rosenbergii

Since the 1990s White Spot Syndrome Virus (WSSV) has severely affected shrimp aquaculture worldwide causing a global pandemic of White Spot Disease (WSD) in penaeid culture. However, not all decapod species that can be infected by WSSV show the same susceptibility to the virus, thus raising interesting questions regarding the potential genetic traits that might confer resistance to WSSV. In order to shed light into the genetic markers of WSSV resistance, we employed a dual approach: i) we initially analysed the transcriptomes derived from the hepatopancreas of two species, the susceptible white shrimp Litopenaeus vannamei and the refractory fresh water prawn Macrobrachium rosenbergii, both infected with WSSV. We found a large number of differentially expressed genes (DEGs) belonging to the immune system (mostly anti-microbial peptides and haemolymph clotting components) that were generally up-regulated in M. rosenbergii and down-regulated in L. vannamei. Further, in both species we identified many up-regulated DEGs that were related to metabolism (suggesting a metabolic shift during the infection) and, interestingly, in L. vannamei only, we found several DEGs that were related to moult and suggested an inhibition of the moult cycle in this species following WSSV infection. ii) we then identified a limited number of genetic markers putatively linked with WSD tolerance by employing an ecological genomics approach in which we compared published reports with our own RNA-seq datasets for different decapod species infected with WSSV. Using this second comparative approach, we found nine candidate genes which are consistently down-regulated in susceptible species and up-regulated in refractory species and which have a role in immune response. Together our data offer novel insights into gene expression differences that can be found in susceptible and refractory decapod species infected with WSSV and provide a valuable resource towards our understanding of the potential genetic basis of tolerance to WSSV.

Increased Cancer Prevalence in Peripartum Cardiomyopathy

ObjectivesThis study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM). BackgroundPPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease. MethodsClinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer. ResultsThe prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes. ConclusionsCardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response–related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients.

The persimmon (Diospyros oleifera Cheng) genome provides new insights into the inheritance of astringency and ancestral evolution

Persimmon (Diospyros kaki) is an oriental perennial woody fruit tree whose popular fruit is produced and consumed worldwide. The persimmon fruit is unique because of the hyperaccumulation of proanthocyanidins during fruit development, causing the mature fruit of most cultivars to have an astringent taste. In this study, we obtained a chromosome-scale genome assembly for ‘Youshi’ (Diospyros oleifera, 2n = 2x = 30), the diploid species of persimmon, by integrating Illumina sequencing, single-molecule real-time sequencing, and high-throughput chromosome conformation capture techniques. The assembled D. oleifera genome consisted of 849.53 Mb, 94.14% (799.71 Mb) of which was assigned to 15 pseudochromosomes, and is the first assembled genome for any member of the Ebenaceae. Comparative genomic analysis revealed that the D. oleifera genome underwent an ancient γ whole-genome duplication event. We studied the potential genetic basis for astringency development (proanthocyanidin biosynthesis) and removal (proanthocyanidin insolublization). Proanthocyanidin biosynthesis genes were mainly distributed on chromosome 1, and the clustering of these genes is responsible for the genetic stability of astringency heredity. Genome-based RNA-seq identified deastringency genes, and promoter analysis showed that most of their promoters contained large numbers of low oxygen-responsive motifs, which is consistent with the efficient industrial application of high CO2 treatment to remove astringency. Using the D. oleifera genome as the reference, SLAF-seq indicated that ‘Youshi’ is one of the ancestors of the cultivated persimmon (2n = 6x = 90). Our study provides significant insights into the genetic basis of persimmon evolution and the development and removal astringency, and it will facilitate the improvement of the breeding of persimmon fruit.

Whole exome sequencing to determine the potential genetic basis of severe early onset pre-eclampsia

Whole exome sequencing to determine the potential genetic basis of severe early onset pre-eclampsia

Parental consanguinity in patients with psychogenic nonepileptic seizures

PurposeThe aim of this study was to investigate the rate of consanguinity of parents of the patients with psychogenic nonepileptic seizures (PNES). This would provide important information for future studies on the potential genetic bases of PNES. MethodsIn this retrospective study, all patients with PNES, who were studied at Shiraz Comprehensive Epilepsy Center at Shiraz University of Medical Sciences, from 2008 to 2018, were recruited. We categorized the patients as (1) no consanguineous marriage of the parents and (2) with consanguineous marriage of the parents. ResultsThree-hundred and sixteen patients had the data on their parental consanguinity available and were studied. The sex ratio (female:male) of the patients was 1.92 (208:108). Parents of 110 (35%) patients had consanguineous marriage, and parents of 206 (65%) patients did not. Demographic variables, seizure-related variables, PNES-associated factors, and the use of antiepileptic drugs were not significantly associated with parental consanguinity in the patients. ConclusionsIn this study, we observed that more than one-third of the patients with PNES had parental consanguinity. This rate is very similar to the rate of consanguinity in the general population in Iran.

Comprehensive Genomic Analysis of Flow-Sorted Hodgkin Reed Sternberg Cells Reveals Additional Genetic Bases of Immune Evasion

Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. Emerging data suggests that cHLs use multiple genetic mechanisms to evade immune recognition. We previously found that HRS cells exhibit near-universal somatic copy number alterations (SCNAs) involving chromosome 9p24.1/PD-1-L1/PD-L2 and rare chromosomal rearrangements of PD-L1 or PD-L2. The 9p24.1 amplicon also includes JAK2, which increases JAK2 copy numbers, augments JAK2/STAT signaling and further induces PD-1 ligand expression.However, HRS cells also have inactivating mutations of B2M and decreased or absent MHC class I expression. In cHL, clinical responses to PD-1 blockade are unrelated to HRS cell expression of MHC class I but closely associated with HRS cell expression of MHC class II, highlighting the potential role of CD4+ T-cell effectors (J Clin Oncol 2018;36:942-50). To define genetic bases of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole exome sequencing (WES) of HRS cells.We first used a previously described multi-color flow cytometric sorting protocol (Methods 2012; 57:368-75) to obtain highly purified CD30+ HRS cells and normal B cells from the excisional biopsies of 25 newly diagnosed cHLs. The isolated HRS cells and paired normal B cells were then subjected to WES using an optimized workflow for low input samples and an expanded bait set to capture structural variants (SVs). We used established analytical pipelines to identify significantly mutated genes (candidate cancer genes [CCGs], MutSig2CV), SCNAs (GISTIC2.0) and SVs (4 algorithms).With improved methodology and purity (median of 80%) of the isolated HRS cells, we defined 15 significantly mutated CCGs, 21 recurrent SCNAs, including 6 CN gains (4 focal and 2 arm level) and 15 CN losses (14 focal and 1 arm level), and low frequency SVs.We identified 2 cHLs as hypermutators with MSI signatures due to splice site mutations in MSH2 or missense mutations in POLE. Excluding the 2 hypermutators, the analyzed cHLs had a median mutational density of 6.4 mutations/Mb, that falls within the top quartile of reported cancer mutational frequencies (Nature 2013 499:214). We also identified a previously unappreciated high incidence of ARID1A mutations (24%) in cHL. This is noteworthy because ARID1A deficiency increases mutational load and augments the efficacy of PD-1 blockade in murine models (Nature Med 2018;24:556). Together, the observed MSI signatures, relatively high mutational burden and newly identified ARID1A mutations in cHL represent additional potential genetic bases for the efficacy of PD-1 blockade.Notably, these cHLs also exhibited recurrent 9p24.1 copy gain (80%) and multiple genetic bases of enhanced JAK/STAT signaling including JAK2 copy gain (80%), STAT6 mutations (32%) involving known hotspots (D419 and N421) in the DNA-binding domain and frequent inactivating SOCS1 mutations (68%).We also identified multiple genetic bases for immune evasion, including B2M inactivating mutations (36%), HLA-B mutations (16%) and 6p21.32/HLA-B copy loss (28%), copy loss of the larger 6p21.32 region and inactivating CIITA SVs (8%).Additional signaling pathways were perturbed by multiple genetic mechanisms in these cHLs. For example, NF-κB pathway alterations included: TNFAIP3 mutations (24%) and 6q23.2/TNFAIP3 copy loss (56%), 12% biallelic; NFKBIE mutations (24%) and 6q21.32/NFKBIE copy loss (12%); and NFKBIA mutations (16%). The gene encoding the nuclear export protein, XPO1, was perturbed by E571K mutations (24%) and frequent 2p15/XPO1 copy gain (72%). Additionally, GNA13, an activator of RHOA and modifier of PI3K signaling, was mutated in 24% of cases.Of interest, cHL recurrent alterations including B2M, TNFAIP3, STAT6, and GNA13 mutations and 6q23.2 and 9p24.1 SCNAs were also identified in > 20% of examined primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases. In summary, comprehensive genomic analyses of purified HRS cells reveal new genetic bases of immune evasion, potential mechanisms of response and resistance to PD-1 blockade and additional targetable alterations.KW, BC, CS, AD and DW contributed equally. JF, GG and MS contributed equally. DisclosuresRodig:Affimed: Research Funding; KITE: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Research Funding. Shipp:Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria.

Population sequencing reveals clonal diversity and ancestral inbreeding in the grapevine cultivar Chardonnay.

Chardonnay is the basis of some of the world’s most iconic wines and its success is underpinned by a historic program of clonal selection. There are numerous clones of Chardonnay available that exhibit differences in key viticultural and oenological traits that have arisen from the accumulation of somatic mutations during centuries of asexual propagation. However, the genetic variation that underlies these differences remains largely unknown. To address this knowledge gap, a high-quality, diploid-phased Chardonnay genome assembly was produced from single-molecule real time sequencing, and combined with re-sequencing data from 15 different Chardonnay clones. There were 1620 markers identified that distinguish the 15 clones. These markers were reliably used for clonal identification of independently sourced genomic material, as well as in identifying a potential genetic basis for some clonal phenotypic differences. The predicted parentage of the Chardonnay haplomes was elucidated by mapping sequence data from the predicted parents of Chardonnay (Gouais blanc and Pinot noir) against the Chardonnay reference genome. This enabled the detection of instances of heterosis, with differentially-expanded gene families being inherited from the parents of Chardonnay. Most surprisingly however, the patterns of nucleotide variation present in the Chardonnay genome indicate that Pinot noir and Gouais blanc share an extremely high degree of kinship that has resulted in the Chardonnay genome displaying characteristics that are indicative of inbreeding.

"Why did I get that part of you?" Understanding addiction genetics through family history.

Scientists have sought to uncover the genetic bases of many diseases and disorders. In response, scholars defined "geneticization" to describe genetic infiltration of understandings of health and illness. In our research, we interviewed 63 individuals in addiction treatment programs to identify what form of geneticization best fits individuals' description of their own addiction. Individuals' narratives of their lives, which include family history and are influenced by cultural and structural factors, affect respondents' reactions to a potential genetic basis of addiction. Most who had a family history of addiction subscribed to a notion that addiction "runs in families," while most who lacked a family history of addiction used this fact to reject the notion of genetic inheritance of addiction. We conclude that though we see elements of several different versions of geneticization, Nikolas Rose's version, that genetics affects peoples' perceptions of addiction in small but important ways, best describes our respondents' views.

Population Genomics Reveals Genetic Divergence and Adaptive Differentiation of Chinese Sea Bass (Lateolabrax maculatus).

The marine species usually show high dispersal capabilities accompanied by high levels of gene flow. On the other hand, many physical barriers distribute along the continental marginal seas and may prevent dispersals and increase population divergence. These complexities along the continental margin generate serious challenges to population genetic studies of marine species. Chinese sea bass Lateolabrax maculatus distributes broad latitudinal gradient spanning from the tropical to the mid-temperate zones in the continental margin seas of the Northwest Pacific Ocean. Using the double digest restriction-site-associated DNA tag sequencing (ddRAD) approach, we genotyped 10,297 SNPs for 219 Chinese seabass individuals of 12 populations along the Chinese coast in the Northwest Pacific region. Genetic divergence among these populations was evaluated, and population structure was established. The results suggested that geographically distant populations in the Bohai Gulf and the Beibu Gulf retain significant genetic divergence, which are connected by a series of intermediate populations in between. The results also suggested that Leizhou Peninsula, Hainan Island, and Shandong Peninsula are major physical barriers and substantially block gene flow and genetic admixture of L. maculatus. We also investigated the potential genetic basis of local adaptation correlating with population differentiation of L. maculatus. The sea surface temperature is a significantly differentiated environmental factor for the distribution of L. maculatus. The correlation of water temperature and genetic variations in extensively distributed populations was investigated with Bayesian-based approaches. The candidate genes underlying the local selection in geographically divergent populations were identified and annotated, providing clues to understand the potential mechanisms of adaptive evolution. Overall, our genome scale population genetic analysis provided insight into population divergence and local adaptation of Chinese sea bass in the continental marginal seas along Chinese coast.

Comparative transcriptomic analysis of Tibetan Gynaephora to explore the genetic basis of insect adaptation to divergent altitude environments

Adaptation of insects to different altitudes remain largely unknown, especially those endemic to the Tibetan Plateau (TP). Here, we generated the transcriptomes of Gynaephora menyuanensis and G. alpherakii, inhabiting different high altitudes on the TP, and used these and the previously available transcriptomic and genomic sequences from low-altitude insects to explore potential genetic basis for divergent high-altitude adaptation in Gynaephora. An analysis of 5,869 orthologous genes among Gynaephora and other three low-altitude insects uncovered that fast-evolving genes and positively selected genes (PSGs) in the two Gynaephora species were enriched in energy metabolism and hypoxia response categories (e.g. mitochondrion, oxidation-reduction process, and response to oxidative stress). Particularly, mTOR signaling pathway involving hypoxia was enriched by PSGs, indicating this well-known pathway in mammal hypoxia adaptation may be an important signaling system in Gynaephora. Furthermore, some PSGs were associated with response to hypoxia (e.g. cytochrome proteins), cold (e.g. dehydrogenase) and DNA repair (e.g. DNA repair proteins). Interestingly, several insect-specific genes that were associated with exoskeleton and cuticle development (e.g. chitinase and ecdysteroids) had experienced positive selection, suggesting the specific adaptive mechanisms in insects. This study is favourable for understanding the adaptive evolution of Gynaephora and even TP insects to divergent altitudes.

Genetic basis of chromosomally-encoded mcr-1 gene

Compared with plasmid-borne mcr-1, the occurrence of chromosomally-encoded mcr-1 is rare although it has been reported in several cases. This study aimed to investigate the genetic features of chromosomally-encoded mcr-1 among Escherichia coli strains as well as the potential genetic basis governing mobilisation of mcr-1 in bacterial chromosomes. The genome sequences of 16 E. coli strains containing a chromosomal mcr-1 gene were obtained and analysed. Phylogenetic and whole-genome sequencing (WGS) analysis demonstrated that mcr-1 was associated with four major types of genetic arrangements, namely ISApl1–mcr1–orf, Tn6330, complex Tn6330 and ΔTn6330 in chromosomes of genetically unrelated E. coli strains. The mcr-1-carrying mobile elements were shown to insert into the AT-rich region, which was also the case for ISApl1. Analysis of complete E. coli genome sequences showed that there were multiple copies of ISApl1 present in E. coli chromosomes that also carried mcr-1, whilst all mcr-1-negative chromosomes were absent of any copy of ISApl1, suggesting the strong association of ISApl1 and mcr-1. Insertion of ISApl1 into E. coli chromosomes may be a prerequisite for the insertion of mcr-1-carrying mobile elements. Insertion of mcr-1 into E. coli chromosomes would enable it to become intrinsically resistant, which is expected to become more prevalent. Policy on the prudent use of colistin both in veterinary and clinical settings should be imposed globally to further prevent dissemination of mcr-1 in E. coli and other bacterial pathogens.

A Genetic Basis of Economic Egalitarianism

Studies of political attitudes and ideologies have sought to explain their origin. They have been assumed to be a result of political values ingrained during the process of socialization until early adulthood, as well as personal political experience, party affiliation, social strata, etc. As a consequence of these environment-dominated explanations, most biology-based accounts of political preference have never been considered. However, in the light of evidence accumulated in recent years, the view that political attitudes are detached from any physical properties became unsustainable. In this paper, we investigate the origins of social justice attitudes, with special focus on economic egalitarianism and its potential genetic basis. We use Minnesota Twin Study data from 2008, collected from samples of monozygotic and dizygotic twin pairs (n = 573) in order to estimate the additive genetic, shared environmental, and unique environmental components of social justice attitudes. Our results show that the large portion of the variance in a four-item economic egalitarianism scale can be attributed to genetic factor. At the same time, shared environment, as a socializing factor, has no significant effect. The effect of environment seems to be fully reserved for unique personal experience. Our findings further problematize a long-standing view that social justice attitudes are dominantly determined by socialization.

Genetic variants of microRNA processing genes and risk of non-syndromic orofacial clefts.

MicroRNA (miRNA) processing genes play important roles in the craniofacial development. The aim of this study was to explore the associations between single nucleotide polymorphisms (SNPs) of miRNA processing genes with the risk of non-syndromic orofacial clefts (NSOC). We genotyped 12 potentially functional SNPs from seven miRNA processing genes (GEMIN3, DROSHA, DGCR8, GEMIN4, PIWIL1, XPO5, and DICER) in a case-control study of 602 NSOC cases and 605 controls. Two SNPs were associated with the susceptibility of CL/P: rs10719 in DROSHA led to an increased risk of cleft lip with or without palate (CL/P) (GA/AA: p=.024, OR=1.33, 95% CI=[1.04, 1.70]; GG+GA/AA: p=.037, OR=1.29, 95% CI=[1.02, 1.63]), while rs493760 in DROSHA (CC/TT: p=.049, OR=0.58, 95% CI=[0.34, 0.99]) could reduce the risk of CL/P. In addition, rs10719 (A)-rs493760 (C) haplotype contributed to a decreased risk of CL/P (OR=0.77, 95% CI=[0.63, 0.94]), whereas the rs10719 (G)-rs493760 (C) haplotype contributed to the increased risk of cleft palate only (CPO) (OR=2.70, 95% CI=[1.15, 6.35]). However, there was no difference observed in these SNPs after the Bonferroni correction. Taken together, our results provided the potential evidence that rs10719 and rs493760 might contribute to the risk of CL/P and suggested potential genetic basis and mechanisms of CL/P. The lack of association between these SNPs and CPO might be due to the limited sample size of CPO subgroup.

Abstract 4261: Cancer in childhood and molecular epidemiology - The KIKME case-control study

Abstract Treatment of first primary neoplasms (PN) in childhood with radiotherapy or chemotherapy is an established risk factor for second primary neoplasms (SN). In addition, there is growing evidence for this association from observational studies on ionizing radiation and cancer risk, in particular after radiation exposure in childhood. As only a subgroup of the treated children suffers from SN, other risk modifying factors (e.g. genetics) must be involved. We are conducting a case-control study with 600 anticipated participants to evaluate gene-radiation interactions and risk of SN (leukemia, thyroid or skin cancer) as well as PN (leukemia, lymphoma or CNS) with a new epidemiological design, in which we combine observational with experimental elements by analyzing gene expression in irradiated cultured human fibroblasts from skin biopsies. In a first step, we examine the participation proportions of survivors of childhood cancer with and without a SN and cancer free control patients (CO) from the department of accident surgery and orthopaedics. In addition to a skin biopsy of 3 mm and a saliva sample, we collect detailed questionnaire information on lifetime exposure to medical radiation and chemotherapy, socio-demographic factors, smoking, drinking, physical activity, medical history and family history of cancer and other diseases. Cases and controls will be matched by sex and age (1:1), and additionally among the former childhood cancer patients by type of the PN and year of first diagnosis (1 SN:3 PN). In explorative pilot experiments, we estimate gene expression differences by RNA-Seq in fibroblasts after low (0.05 Gy) and high (2 Gy) radiation doses at different time points (0.25 h, 2 h, 24 h). In the first recruitment drives of the ongoing study, we recruited 77 patients with SN and 95 matched patients with only one PN from 1975 eligible former childhood cancer patients at the German Childhood Cancer Registry, as well as 22 CO patients. Until November 2016, 33% of the contacted 231 SN patients, 20% of the 486 contacted PN patients and 69% of the 32 contacted CO patients participated in our study. Two hours after low and high in vitro radiation doses, the largest number of genes were differentially expressed, some of them only after high doses, some only after low doses and some after both. To our knowledge, the KIKME study is the first epidemiological project analyzing differential gene expression in primary fibroblasts before and after radiation with high and low doses to evaluate the potential genetic basis for emergence of a SN and a PN. However, the biological importance of the suggested differential gene expression after high and low doses of radiation has to be confirmed with the full study population. In addition, the gene expression must be analyzed in detail by group (SN, PN, CO) and will be combined with results from whole genome sequencing in order to obtain a comprehensive view of the role of radiation in the carcinogenesis of childhood cancer. Citation Format: Manuela Marron, Sebastian Zahnreich, Olesja Sinizyn, Heinz Schmidberger, Moritz Hess, Patricia Sadre Dadras, Iris Altebockwinkel, Thomas Hankeln, Steffen Rapp, Anne Ebersberger, Christian Grad, Eva Holzhäuser, Lukas Eckhard, Dirk Proschek, Maria Blettner, Peter Kaatsch, Claudia Spix, Danuta Galetzka, Harald Binder. Cancer in childhood and molecular epidemiology - The KIKME case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4261. doi:10.1158/1538-7445.AM2017-4261

Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome

ANGPTL8 is a liver-derived protein related to insulin-sensitivity. Its relationship with obesity and liver function in Prader-Willi syndrome (PWS) is unknown. The present study investigated circulating ANGPTL8 in PWS and controls with common obesity, assessing its association to liver steatosis. For this purpose, 20 obese PWS and 20 controls matched for body mass index (BMI), sex and age underwent analysis of ANGPTL8 levels, glucose and lipid metabolism. Liver function tests and degree of liver steatosis by ultrasonography (US), fat-free mass (FFM) and fat mass (FM) by dual-energy x-ray absorptiometry (DEXA) were also assessed. In comparison to controls, obese PWS showed lower values of FFM (p < 0.0001) and higher FM (p = 0.01), while harbouring higher HDL cholesterol, lower triglycerides and OGTT-derived insulin levels, as well as a lower prevalence and severity of liver steatosis. With respect to obese controls, ANGPTL8 levels were significantly lower in PWS (p = 0.007) and overall correlated with transaminase levels and the severity of liver steatosis, as well as FFM (p < 0.05 for all). By a stepwise multivariable regression analysis, ANGPTL8 levels were independently predicted by PWS status (p = 0.01) and liver steatosis (p < 0.05). In conclusion, ANGPTL8 levels are lower in PWS than obese controls and are inversely associated with the severity of liver steatosis. Further studies should investigate the potential genetic basis for this observation.

The caterpillar fungus, Ophiocordyceps sinensis, genome provides insights into highland adaptation of fungal pathogenicity

To understand the potential genetic basis of highland adaptation of fungal pathogenicity, we present here the ~116 Mb de novo assembled high-quality genome of Ophiocordyceps sinensis endemic to the Qinghai-Tibetan Plateau. Compared with other plain-dwelling fungi, we find about 3.4-fold inflation of the O. sinensis genome due to a rapid amplification of long terminal repeat retrotransposons that occurred ~38 million years ago in concert with the uplift of the plateau. We also observe massive removal of thousands of genes related to the transport process and energy metabolism. O. sinensis displays considerable lineage-specific expansion of gene families functionally enriched in the adaptability of low-temperature of cold tolerance, fungal pathogenicity and specialized host infection. We detect signals of positive selection for genes involved in peroxidase and hypoxia to enable its highland adaptation. Resequencing and analyzing 31 whole genomes of O. sinensis, representing nearly all of its geographic range, exhibits latitude-based population divergence and nature selection for population inhabitation towards higher altitudes on the Qinghai-Tibetan Plateau.