Τετάρτη, 1 Μαΐου 2019

Genes Genetics Genomics

Rapid identification of a candidate nicosulfuron sensitivity gene ( Nss ) in maize ( Zea mays L.) via combining bulked segregant analysis and RNA-seq

Abstract

Key message

A candidate nicosulfuron sensitivity gene Nss was identified by combining bulked segregant analysis and RNA-seq. Multiple mutations of this gene were discovered in nicosulfuron-sensitive maize compared with the tolerant.

Abstract

It has been demonstrated that variabilities exist in maize response to nicosulfuron. Two nicosulfuron-sensitive inbred lines (HB39, HB41) and two tolerant inbred lines (HB05, HB09) were identified via greenhouse and field trials. Genetic analysis indicated that the sensitivity to nicosulfuron in maize was controlled by a single, recessive gene. To precisely and rapidly map the nicosulfuron sensitivity gene (Nss), two independent F2 segregating populations, Population A (HB41 × HB09) and Population B (HB39 × HB05), were constructed. By applying bulked segregant RNA-Seq (BSR-Seq), the Nss gene was, respectively, mapped on the short arm of chromosome 5 (chr5: 1.1–15.3 Mb) and (chr5: 0.5–18.2 Mb) using two populations, with 14.2 Mb region in common. Further analysis revealed that there were 43 and 119 differentially expressed genes in the mapping intervals, with 18 genes in common. Gene annotation results showed that a cytochrome P450 gene (CYP81A9) appeared to be the candidate gene of Nss associated with nicosulfuron sensitivity in maize. Sequence analysis demonstrated that two common deletion mutations existed in the sensitive maize, which might lead to the nicosulfuron sensitivity in maize. The results will make valuable contributions to the understanding of molecular mechanism of herbicide sensitivity in maize.



Assessment of breeding programs sustainability: application of phenotypic and genomic indicators to a North European grain maize program

Abstract

Key message

We review and propose easily implemented and affordable indicators to assess the genetic diversity and the potential of a breeding population and propose solutions for its long-term management.

Abstract

Successful plant breeding programs rely on balanced efforts between short-term goals to develop competitive cultivars and long-term goals to improve and maintain diversity in the genetic pool. Indicators of the sustainability of response to selection in breeding pools are of key importance in this context. We reviewed and proposed sets of indicators based on temporal phenotypic and genotypic data and applied them on an early maize grain program implying two breeding pools (Dent and Flint) selected in a reciprocal manner. Both breeding populations showed a significant positive genetic gain summing up to 1.43 qx/ha/year but contrasted evolutions of genetic variance. Advances in high-throughput genotyping permitted the identification of regions of low diversity, mainly localized in pericentromeric regions. Observed changes in genetic diversity were multiple, reflecting a complex breeding system. We estimated the impact of linkage disequilibrium (LD) and of allelic diversity on the additive genetic variance at a genome-wide and chromosome-wide scale. Consistently with theoretical expectation under directional selection, we found a negative contribution of LD to genetic variance, which was unevenly distributed between chromosomes. This suggests different chromosome selection histories and underlines the interest to recombine specific chromosome regions. All three sets of indicators valorize in house data and are easy to implement in the era of genomic selection in every breeding program.



GWAS analysis of sorghum association panel lines identifies SNPs associated with disease response to Texas isolates of Colletotrichum sublineola

Abstract

Key message

SNPs identify prospective genes related to response to Colletotrichum sublineola (anthracnose) in the sorghum association panel lines.

Abstract

Sorghum association panel (SAP) lines were scored over several years for response to Colletotrichum sublineola, the causal agent of the disease anthracnose. Known resistant and susceptible lines were included each year to verify successful inoculation. Over 79,000 single-nucleotide polymorphic (SNP) loci from a publicly available genotype by sequencing dataset available for the SAP lines were used with TASSEL association mapping software to identify chromosomal locations associated with differences in disease response. When the top-scoring SNPs were mapped to the published sorghum genome, in each case, the nearest annotated gene has precedence for a role in host defense.



QTL mapping of resistance to bacterial fruit blotch in Citrullus amarus

Abstract

Key message

Six QTLs were associated with affected leaf area in response to inoculation with Acidovorax citrulli in a recombinant inbred line population of Citrullus amarus.

Abstract

Acidovorax citrulli, the causal agent of bacterial fruit blotch (BFB) of cucurbits, has the potential to devastate production of watermelon and other cucurbits. Despite decades of research on host-plant resistance to A. citrulli, no germplasm has been found with immunity and only a few sources with various levels of BFB resistance have been identified, but the genetic basis of resistance in these watermelon sources are not known. Most sources of resistance are plant introductions of Citrullus amarus (citron melon), a closely related species that crosses readily with cultivated watermelon (Citrullus lanatus L.). In this study, we evaluated a recombinant inbred line population (N = 200), derived from a cross between BFB-resistant (USVL246-FR2) and BFB-susceptible (USVL114) C. amarus lines, for foliar resistance to A. citrulli in three replicated greenhouse trials. We found the genetics of BFB resistance to be complicated by strong environmental influence, low heritability and significant genotype-by-environment interactions. QTL mapping of affected leaf area identified six QTL that each explained between 5 and 15% of the variation in BFB resistance in the population. This study represents the first identification of QTL associated with resistance to Acitrulli in any cucurbit.



A major QTL co-localized on chromosome 6BL and its epistatic interaction for enhanced wheat stripe rust resistance

Abstract

Key message

Co-localization of a major QTL for wheat stripe rust resistance to a 3.9-cM interval on chromosome 6BL across both populations and another QTL on chromosome 2B with epistatic interaction.

Abstract

Cultivars with diverse resistance are the optimal strategy to minimize yield losses caused by wheat stripe rust (Puccinia striiformis f. sp. tritici). Two wheat populations involving resistant wheat lines P10078 and Snb"S" from CIMMYT were evaluated for stripe rust response in multiple environments. Pool analysis by Wheat660K SNP array showed that the overlapping interval on chromosome 6B likely harbored a major QTL between two populations. Then, linkage maps were constructed using KASP markers, and a co-localized locus with large effect on chromosome 6BL was detected using QTL analysis in both populations. The coincident QTL, named QYr.nwafu-6BL.2, explained 59.7% of the phenotypic maximum variation in the Mingxian 169 × P10078 and 52.5% in the Zhengmai 9023 × Snb"S" populations, respectively. This co-localization interval spanning 3.9 cM corresponds to ~ 30.5-Mb genomic region of the newest common wheat reference genome (IWGSC RefSeq v.1.0). In addition, another QTL was also detected on chromosome 2B in Zhengmai 9023 × Snb"S" population and it can accelerate expression of QYr.nwafu-6BL.2 to enhance resistance with epistatic interaction. Allowing for Pst response, marker genotypes, pedigree analysis and relative genetic distance, QYr.nwafu-6BL.2 is likely to be a distinct adult plant resistance QTL. Haplotype analysis of QYr.nwafu-6BL.2 revealed specific SNPs or alleles in the target region from a diversity panel of 176 unrelated wheat accessions. This QTL region provides opportunity for further map-based cloning, and haplotypes analysis enables pyramiding favorable alleles into commercial cultivars by marker-assisted selection.



Identification of quantitative trait loci governing subgynoecy in cucumber

Abstract

Key message

QTL-seq analysis identified three major QTLs conferring subgynoecy in cucumbers. Furthermore, sequence and expression analyses predicted candidate genes controlling subgynoecy.

Abstract

The cucumber (Cucumis sativus L.) is a typical monoecious having individual male and female flowers, and sex differentiation is an important developmental process that directly affects its fruit yield. Subgynoecy represents a sex form with a high degree of femaleness and would have alternative use as gynoecy under limited resource conditions. Recently, many studies have been reported that QTL-seq, which integrates the advantages of bulked segregant analysis and high-throughput whole-genome resequencing, can be a rapid and cost-effective way of mapping QTLs. Segregation analysis in the F2 and BC1 populations derived from a cross between subgynoecious LOSUAS and monoecious BMB suggested the quantitative nature of subgynoecy in cucumbers. Both genome-wide SNP profiling of subgynoecious and monoecious bulks constructed from F2 and BC1plants consistently identified three significant genomic regions, one on chromosome 3 (sg3.1) and another two on short and long arms of chromosome 1 (sg1.1 and sg1.2). Classical QTL analysis using the F2 confirmed sg3.1 (R2 = 42%), sg1.1 (R2 = 29%) and sg1.2 (R2 = 18%) as major QTLs. These results revealed the unique genetic inheritance of subgynoecious line LOSUAS through two distinct major QTLs, sg3.1 and sg1.1, which mainly increase degree of femaleness, while another QTL, sg1.2, contributes to decrease it. This study demonstrated that QTL-seq allows rapid and powerful detection of QTLs using preliminary generation mapping populations such as F2 or BC1 population and further that the identified QTLs could be useful for molecular breeding of cucumber lines with high yield potential.



Identification and validation of a novel major QTL for all-stage stripe rust resistance on 1BL in the winter wheat line 20828

Abstract

Key message

A major, likely novel stripe rust resistance QTL for all-stage resistance on chromosome arm 1BL identified in a 1.76-cM interval using a saturated linkage map was validated in four populations with different genetic backgrounds.

Abstract

Stripe rust is a globally important disease of wheat. Identification and utilization of new resistance genes are essential for breeding resistant cultivars. Wheat line 20828 has exhibited high levels of stripe rust resistance for over a decade. However, the genetics of stripe rust resistance in this line has not been studied. A set of 199 recombinant inbred lines (RILs) were developed from a cross between 20828 and a susceptible cultivar Chuannong 16. The RIL population was genotyped with the Wheat55K SNP (single nucleotide polymorphism) array and SSR (simple sequence repeat) markers and evaluated in four environments with current predominant Puccinia striiformis f. sp. tritici t races including CYR32, CYR33 and CYR34. Four stable QTL were located on chromosomes 1B (2 QTL), 4A and 6A. Among them, the major QTL, QYr.sicau-1B.1 (LOD = 23–28, PVE = 16–39%), was localized to a 1.76-cM interval flanked by SSR markers Xwmc216 and Xwmc156 on chromosome 1BL. Eight resistance genes were previously identified in the physical interval of QYr.sicau-1B.1. Compared with previous studies, QYr.sicau-1B.1 is a new gene for resistant to stripe rust. It was further verified by analysis of the closely linked SSR markers Xwmc216 and Xwmc156 in four other populations with different genetic backgrounds. QYr.sicau-1B.1 reduced the stripe rust disease index by up to 82.8%. Three minor stable QTL (located on chromosomes 1B, 4A and 6A, respectively) also added to the resistance level of QYr.sicau-1B.1. Our results provide valuable information for further fine mapping and cloning as well as molecular-assisted breeding with QYr.sicau-1B.1.



Fine mapping of Rha2 in barley reveals candidate genes for resistance against cereal cyst nematode

Abstract

Key message

The cereal cyst nematode resistance locus Rha2 was mapped to a 978 kbp region on the long arm of barley chromosome 2H. Three candidate genes are discussed.

Abstract

The cereal cyst nematode (CCN) Heterodera avenae is a soil-borne obligate parasite that can cause severe damage to cereals. This research involved fine mapping of Rha2, a CCN resistance locus on chromosome 2H of barley. Rha2 was previously mapped relative to restriction fragment length polymorphisms (RFLPs) in two mapping populations. Anchoring of flanking RFLP clone sequences to the barley genome assembly defined an interval of 5077 kbp. Genotyping-by-sequencing of resistant and susceptible materials led to the discovery of potentially useful single nucleotide polymorphisms (SNPs). Assays were designed for these SNPs and applied to mapping populations. This narrowed the region of interest to 3966 kbp. Further fine mapping was pursued by crossing and backcrossing the resistant cultivar Sloop SA to its susceptible ancestor Sloop. Evaluation of F2progeny confirmed that the resistance segregates as a single dominant gene. Genotyping of 9003 BC2F2 progeny identified recombinants. Evaluation of recombinant BC2F3 progeny narrowed the region of interest to 978 kbp. Two of the SNPs within this region proved to be diagnostic of CCN resistance across a wide range of barley germplasm. Fluorescence-based and gel-based assays were developed for these SNPs for use in marker-assisted selection. Within the candidate region of the reference genome, there are nine high-confidence predicted genes. Three of these, one that encodes RAR1 (a cysteine- and histidine-rich domain-containing protein), one that is predicted to encode an acetylglutamate kinase and one that is predicted to encode a tonoplast intrinsic protein, are discussed as candidate genes for CCN resistance.



Identification and characterization of a new dwarf locus DS - 4 encoding an Aux/IAA7 protein in Brassica napus

Abstract

Key message

A dominant dwarfing gene, ds - 4 , encodes an Aux/IAA protein that negatively regulates plant stature through an auxin signaling pathway.

Abstract

Dwarfism is an important agronomic trait affecting yield in many crop species. The molecular mechanisms underlying dwarfism in oilseed rape (Brassica napus) are poorly understood, restricting the progress of breeding dwarf varieties in this species. Here, we identified and characterized a new dwarf locus, DS-4, in B. napus. Next-generation sequencing-assisted genetic mapping and candidate gene analysis found that DS-4 encodes a nucleus-targeted auxin/indole-3-acetic acid (Aux/IAA) protein. A substitution (P87L) was found in the highly conserved degron motif of the Aux/IAA7 protein in the ds-4 mutant. This mutation co-segregated with the phenotype of individuals in the BC1F2 population. The P87L substitution was confirmed as the cause of the extreme dwarf phenotype by ectopic expression of the mutant allele BnaC05.iaa7 (equivalent to ds-4) in Arabidopsis. The P87L substitution blocked the interaction of BnaC05.iaa7 with TRANSPORT INHIBITOR RESPONSE 1 in the presence of auxin. The BnaC05.IAA7 gene is highly expressed in the cotyledons, hypocotyls, stems and leaves, but weakly in the roots and seeds of B. napus. Our findings provide new insights into the molecular mechanisms underlying dominant (gain-of-function) dwarfism in B. napus. Our identification of a distinct gene locus controlling plant height may help to improve lodging resistance in oilseed rape.



Ty - 6 , a major begomovirus resistance gene on chromosome 10, is effective against Tomato yellow leaf curl virus and Tomato mottle virus

Abstract

Key message

Ty-6 is a major resistance gene on chromosome 10 of tomato that provides resistance against monopartite and bipartite begomoviruses and complements resistance conferred by the known Ty-3 and ty-5 genes.

Abstract

Resistance to monopartite and bipartite begomoviruses is an important breeding objective for cultivated tomato. Several begomovirus resistance genes have been introgressed from related Solanum species and are available for breeding purposes. In the present study, we mapped an additional locus, Ty-6, to chromosome 10 of tomato. Ty-6 is effective against both monopartite Tomato yellow leaf curl virus (TYLCV) and bipartite Tomato mottle virus (ToMoV). Gene action is incomplete dominance, with an intermediate resistance response when Ty-6 is heterozygous. Analysis of populations segregating for Ty-6 along with Ty-3 or ty-5 indicates that the highest level of resistance against TYLCV is attained when Ty-6 is combined with an additional resistance allele. Our results also demonstrate that ty-5 is ineffective against ToMoV. Although multiple SNPs linked to Ty-6were identified and can be used for breeding purposes, none of these were consistently polymorphic between Ty-6 and ty-6 breeding lines. Further research is underway to generate resequencing data for several Ty-6inbred lines for the discovery of additional sequence polymorphisms that can be used for fine mapping and characterizing the Ty-6 locus.


Identification of placental genes linked to selective intrauterine growth restriction (IUGR) in dichorionic twin pregnancies: gene expression profiling study

Abstract

A linkage of dichorionic (DC) twin pregnancies with selective intrauterine growth restriction (IUGR) to alterations in placental gene expression is unclear. The aim of the study was to identify placental genes related to hypoxia, adipogenesis and human growth which may contribute to IUGR development. The study group (IUGR/AGA) comprised dichorionic (DC) twin pregnancies, where the weight of the twins differed by > 15%; in addition, one twin was small for gestational age (< 10th percentile-SGA) (IUGR) while the other was appropriate for gestational age (> 10th percentile-AGA). In the control group (AGA/AGA), both fetuses were AGA and their weights differed by < 15%. In the first step (selection), placental expression of 260 genes was analysed by commercial PCR profiler array or qPCR primer assay between six pairs of IUGR/AGA twins. In the second stage (verification), the expression of 20 genes with fold change (FC) > 1.5 selected from the first stage was investigated for 75 DC pregnancies: 23 IUGR/AGA vs. 52 AGA/AGA. The expression of Angiopoetin 2, Leptin and Kruppel-like factor 4 was significantly higher, and Glis Family Zinc Finger 3 was lower, in placentas of SGA fetuses (FC = 3.3; 4.4; 1.6; and − 1.8, respectively; p < 0.05). The dysregulation of gene expression related to angiogenesis and growth factors in placentas of twins born from IUGR/AGA pregnancies suggest that these alternations might represent biological fetal adaptation to the uteral condition. Moreover, DC twin pregnancies may be a good model to identify the differences in placental gene expression between SGA and AGA fetuses.



Personalized medicine: going to the dogs?

Abstract

Interindividual variation in drug response occurs in canine patients just as it does in human patients. Although canine pharmacogenetics still lags behind human pharmacogenetics, significant life-saving discoveries in the field have been made over the last 20 years, but much remains to be done. This article summarizes the available published data about the presence and impact of genetic polymorphisms on canine drug transporters, drug-metabolizing enzymes, drug receptors/targets, and plasma protein binding while comparing them to their human counterparts when applicable. In addition, precision medicine in cancer treatment as an application of canine pharmacogenetics and pertinent considerations for canine pharmacogenetics testing is reviewed. The field is poised to transition from single pharmacogene-based studies, pharmacogenetics, to pharmacogenomic-based studies to enhance our understanding of interindividual variation of drug response in dogs. Advances made in the field of canine pharmacogenetics will not only improve the health and well-being of dogs and dog breeds, but may provide insight into individual drug efficacy and toxicity in human patients as well.



Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

Abstract

Replicable genetic association signals have consistently been found through genome-wide association studies in recent years. The recent dramatic expansion of study sizes improves power of estimation of effect sizes, genomic prediction, causal inference, and polygenic selection, but it simultaneously increases susceptibility of these methods to bias due to subtle population structure. Standard methods using genetic principal components to correct for structure might not always be appropriate and we use a simulation study to illustrate when correction might be ineffective for avoiding biases. New methods such as trans-ethnic modeling and chromosome painting allow for a richer understanding of the relationship between traits and population structure. We illustrate the arguments using real examples (stroke and educational attainment) and provide a more nuanced understanding of population structure, which is set to be revisited as a critical aspect of future analyses in genetic epidemiology. We also make simple recommendations for how problems can be avoided in the future. Our results have particular importance for the implementation of GWAS meta-analysis, for prediction of traits, and for causal inference.



EDAR , LYPLAL1 , PRDM16 , PAX3 , DKK1 , TNFSF12 , CACNA2D3 , and SUPT3H gene variants influence facial morphology in a Eurasian population

Abstract

In human society, the facial surface is visible and recognizable based on the facial shape variation which represents a set of highly polygenic and correlated complex traits. Understanding the genetic basis underlying facial shape traits has important implications in population genetics, developmental biology, and forensic science. A number of single nucleotide polymorphisms (SNPs) are associated with human facial shape variation, mostly in European populations. To bridge the gap between European and Asian populations in term of the genetic basis of facial shape variation, we examined the effect of these SNPs in a European–Asian admixed Eurasian population which included a total of 612 individuals. The coordinates of 17 facial landmarks were derived from high resolution 3dMD facial images, and 136 Euclidean distances between all pairs of landmarks were quantitatively derived. DNA samples were genotyped using the Illumina Infinium Global Screening Array and imputed using the 1000 Genomes reference panel. Genetic association between 125 previously reported facial shape-associated SNPs and 136 facial shape phenotypes was tested using linear regression. As a result, a total of eight SNPs from different loci demonstrated significant association with one or more facial shape traits after adjusting for multiple testing (significance threshold p < 1.28 × 10−3), together explaining up to 6.47% of sex-, age-, and BMI-adjusted facial phenotype variance. These included EDAR rs3827760, LYPLAL1 rs5781117, PRDM16 rs4648379, PAX3 rs7559271, DKK1 rs1194708, TNFSF12 rs80067372, CACNA2D3 rs56063440, and SUPT3H rs227833. Notably, the EDAR rs3827760 and LYPLAL1 rs5781117 SNPs displayed significant association with eight and seven facial phenotypes, respectively (2.39 × 10−5 < p < 1.28 × 10−3). The majority of these SNPs showed a distinct allele frequency between European and East Asian reference panels from the 1000 Genomes Project. These results showed the details of above eight genes influence facial shape variation in a Eurasian population.



The Four Horsemen of the 'Omicsalypse': ontology, replicability, probability and epistemology

Abstract

Much of modern genomics and the other 'omics' that tag along, assert that the causal bases of biomedical outcomes are genomically enumerable lists whose effects are predictable with 'precision', extensible from samples to all, and enabled by ever-greater hypothesis-free data accumulation. The assertion rests on fundamental, if often implicit assumptions, that (1) the phenomena are based on underlying law-like biological causation, and, therefore, are (2) replicable and (3) even if not deterministic, have specifiable, stable, essentially parametric, probabilities, all of which (4) essentially equates induction with deduction, enabling asymptotically accurate prediction based on past observation. These glowing promises are the four horsemen of a genocentric 'Omicsalypse'. But what if the assumptions are wrong or appropriate only to an extent that is unknowable, even in principle? Might there be better ways to understand complex traits?



Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly

Abstract

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.



Quality assurance checklist and additional considerations for canine clinical genetic testing laboratories: a follow-up to the published standards and guidelines

Abstract

There is currently no oversight for canine clinical genetic testing laboratories. We published an initial set of standards and guidelines with the goal of providing a basis for which canine testing laboratories could evaluate their quality assurance programs. To further those standards and guidelines, we have developed a checklist that can be used as a self-evaluation to identify gaps in their programs for continual quality improvement over time. Because there is currently no organization willing to oversee an external proficiency program, the checklist provides the first step toward an internal, self-assessment that can be used periodically to monitor improvements. In addition, we attempt to address concerns from the canine community regarding rare or private mutations, genetic screening using array-based technologies, non-peer reviewed tests that are being offered, and the clinical validity of certain mutations in particular breeds. Through coordination, conversation and hard work, the canine genetic testing community can strive to organize to improve testing and to provide more transparency to consumers and better outcomes for dogs.



Prediction of skin color, tanning and freckling from DNA in Polish population: linear regression, random forest and neural network approaches

Abstract

Predicting phenotypes from DNA has recently become extensively studied field in forensic research and is referred to as Forensic DNA Phenotyping. Systems based on single nucleotide polymorphisms for accurate prediction of iris, hair and skin color in global population, independent of bio-geographical ancestry, have recently been introduced. Here, we analyzed 14 SNPs for distinct skin pigmentation traits in a homogeneous cohort of 222 Polish subjects. We compared three different algorithms: General Linear Model based on logistic regression, Random Forest and Neural Network in 18 developed prediction models. We demonstrate Random Forest to be the most accurate algorithm for 3- and 4-category estimations (total of 58.3% correct calls for skin color prediction, 47.2% for tanning prediction, 50% for freckling prediction). Binomial Logistic Regression was the best approach in 2-category estimations (total of 69.4% correct calls, AUC = 0.673 for tanning prediction; total of 52.8% correct calls, AUC = 0.537 for freckling prediction). Our study confirms the association of rs12913832 (HERC2) with all three skin pigmentation traits, but also variants associated solely with certain pigmentation traits, namely rs6058017 and rs4911414 (ASIP) with skin sensitivity to sun and tanning abilities, rs12203592 (IRF4) with freckling and rs4778241 and rs4778138 (OCA2) with skin color and tanning. Finally, we assessed significant differences in allele frequencies in comparison with CEU data and our study provides a starting point for the development of prediction models for homogeneous populations with less internal differentiation than in the global predictive testing.



A review of gene-by-air pollution interactions for cardiovascular disease, risk factors, and biomarkers

Abstract

Air pollution is recognized as causal factor for cardiovascular disease (CVD) and is associated with multiple CVD risk factors. Substantial research effort has been invested in understanding the linkages between genetic variation and CVD risk, resulting in over 50 CVD-associated genetic loci. More recently, gene–air pollution interaction studies have quantified the contribution of genetic variation to inter-individual heterogeneity in air pollution health risks, and aided in elucidating mechanisms of air pollution exposure health risks. Here, we perform a comprehensive review of gene–air pollution interaction studies for CVD, as well as risk factors and emerging CVD biomarkers. The literature review revealed that most published interaction studies have been candidate gene studies, causing observed interactions to cluster in a few genes related to detoxification (GSTM1and GSTT1), inflammation (IL-6), iron processing (HFE), and microRNA processing (GEMIN4 and DGCR8). There have been a few genome-wide interaction studies with results indicating that interactions extend beyond commonly considered genetic loci. Gene–air pollution interactions are observed for exposure periods ranging from hours to years and a variety of air pollutants including particulate matter, gaseous pollutants, and pollutant sources such as traffic. Though the existing evidence for the existence of relevant gene–air pollution interactions for CVD outcomes is substantial, it could be strengthened by improved replication and meta-analyses as well as functional validation.



Mutation signatures in germline mitochondrial genome provide insights into human mitochondrial evolution and disease

Abstract

Variations in mitochondrial DNA (mtDNA) have been fundamental for understanding human evolution and are causative for a plethora of inherited mitochondrial diseases, but the mutation signatures of germline mtDNA and their value in understanding mitochondrial pathogenicity remain unknown. Here, we carried out a systematic analysis of mutation patterns in germline mtDNA based on 97,566 mtDNA variants from 45,494 full-length sequences and revealed a highly non-stochastic and replication-coupled mutation signature characterized by nucleotide-specific mutation pressure (G > T>A > C) and position-specific selection pressure, suggesting the existence of an intensive mutation–selection interplay in germline mtDNA. We provide evidence that this mutation–selection interplay has strongly shaped the mtDNA sequence during evolution, which not only manifests as an oriented alteration of amino acid compositions of mitochondrial encoded proteins, but also explains the long-lasting mystery of CpG depletion in mitochondrial genome. Finally, we demonstrated that these insights may be integrated to better understand the pathogenicity of disease-implicated mitochondrial variants.


Immune stimulation of rainbow trout reveals divergent regulation of MH class II-associated invariant chain isoforms

Abstract

Major histocompatibility complex (MHC) class II-associated invariant chain is a chaperone responsible for targeting the MHC class II dimer to the endocytic pathway, thus enabling the loading of exogenous antigens onto the MHC class II receptor. In the current study, in vivo and in vitro methods were used to investigate the regulation of the rainbow trout invariant chain proteins S25-7 and INVX, upon immune system activation. Whole rainbow trout and the macrophage/monocyte-like cell line RTS11 were treated with PMA at concentrations shown to induce IL-1β transcripts and homotypic aggregation of RTS11. S25-7 transcript levels remained unchanged in the gill, spleen, and liver and were found to be significantly decreased in head kidney beginning 24 h post-stimulation. Meanwhile, INVX transcript levels remained unchanged in all tissues studied. Both S25-7 and INVX proteins were produced in gill and spleen tissues but their expression was unaffected by immune system stimulation. Surprisingly, neither INVX nor S25-7 protein was detected in the secondary immune organ, the head kidney. Analysis of RTS11 cultures demonstrated that both INVX and S25-7 transcript levels significantly increased at 96 h and 120 h following PMA stimulation before returning to control levels at 168 h. Meanwhile, at the protein level in RTS11, S25-7 remained unchanged while INVX had a significant decrease at 168 h post-stimulation. These results indicate that neither INVX nor S25-7 is upregulated upon immune system activation; thus, teleosts have evolved a system of immune regulation that is different than that found in mammals.



Correction to: HLA-F*01:01 presents peptides with N-terminal flexibility and a preferred length of 16 residues

The original version of this article contained errors. The Article Title, Figures 1 and 3, and Electronic Supplementary Materials were incorrectly shown in the wrong version. The original article has been corrected.



DLA class II haplotypes show sex-specific associations with primary hypoadrenocorticism in Standard Poodle dogs

Abstract

Addison's disease (AD) is a life-threatening endocrine disorder that occurs spontaneously in both humans and dogs. Associations between MHC class II genes and AD have been shown in several human studies. Our goal was to identify MHC class II associations with AD in a large population of Standard Poodles, a breed highly predisposed to AD. We sequenced exon 2 of the class II genes DLA-DRB1, DLA-DQA1, and DLA-DQB1 in 110 affected and 101 unaffected Standard Poodles and tested for association with AD. After correcting for population structure, two haplotypes were found to confer risk of developing AD in a sex-specific manner: DLA-DRB1*015:01-DQA1*006:01-DQB1*023:01 in males (x2p = 0.03, OR 2.1) and DLA-DRB1*009:01-DQA1*001:01-DQB1*008:01:1 in females (x2p = 0.02, OR 8.43). Sex-specific associations have been previously described in human populations, but this is the first report of this kind in dogs. Consistent with findings in other studies, we found the DLA-DQA1*006:01 allele (x2p = 0.04) to be associated with AD in males independent of haplotype. In females, the haplotype DLA-DRB1*009:01-DQA1*001:01-DQB1*008:01:1 confers a very high risk for developing AD, although its frequency was rare (9 of 124 females) in our study population. Further studies are warranted to validate the findings of this exploratory dataset and to assess the usefulness of this haplotype as a risk marker for AD in female Standard Poodles. Our results highlight the importance of evaluating MHC class II disease associations in large populations, and accounting for both biological sex and population structure.



Distribution of ancient α1 and α2 domain lineages between two classical MHC class I genes and their alleles in grass carp

Abstract

Major histocompatibility complex (MHC) class I molecules play a crucial role in the immune response by binding and presenting pathogen-derived peptides to specific CD8+ T cells. From cDNA of 20 individuals of wild grass carp (Ctenopharyngodon idellus), we could amplify one or two alleles each of classical MHC class I genes Ctid-UAA and Ctid-UBA. In total, 27 and 22 unique alleles of Ctid-UAA and Ctid-UBA were found. The leader, α1, transmembrane and cytoplasmic regions distinguish between Ctid-UAA and Ctid-UBA, and their encoded α1 domain sequences belong to the ancient lineages α1-V and α1-II, respectively, which separated several hundred million years ago. However, Ctid-UAA and Ctid-UBA share allelic lineage variation in their α2 and α3 sequences, in a pattern suggestive of past interlocus recombination events that transferred α2+α3 fragments. The allelic Ctid-UAA and Ctid-UBA variation involves ancient variation between domain lineages α2-I and α2-II, which in the present study was dated back to before the ancestral separation of teleost fish and spotted gar (> 300 million years ago). This is the first report with compelling evidence that recombination events combining different ancient α1 and α2 domain lineages had a major impact on the allelic variation of two different classical MHC class I genes within the same species.



HLA-F*01:01 presents peptides with N-terminal flexibility and a preferred length of 16 residues

Abstract

HLA-F belongs to the non-classical HLA-Ib molecules with a marginal polymorphic nature and tissue-restricted distribution. HLA-F is a ligand of the NK cell receptor KIR3DS1, whose activation initiates an antiviral downstream immune response and lead to delayed disease progression of HIV-1. During the time course of HIV infection, the expression of HLA-F is upregulated while its interaction with KIR3DS1 is diminished. Understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response and the molecules function. In this study, we were able to recover stable pHLA-F*01:01 complexes and analyze the characteristics of peptides naturally presented by HLA-F. These HLA-F-restricted peptides exhibit a non-canonical length without a defined N-terminal anchor. The peptide characteristics lead to a unique presentation profile and influence the stability of the protein. Furthermore, we demonstrate that almost all source proteins of HLA-F-restricted peptides are described to interact with HIV proteins. Understanding the balance switch between HLA-Ia and HLA-F expression and peptide selection will support to understand the role of HLA-F in viral pathogenesis.



Functional variation at an expressed MHC class IIβ locus associates with Ranavirus infection intensity in larval anuran populations

Abstract

Infectious diseases are causing catastrophic losses to global biodiversity. Iridoviruses in the genus Ranavirus are among the leading causes of amphibian disease-related mortality. Polymorphisms in major histocompatibility complex (MHC) genes are significantly associated with variation in amphibian pathogen susceptibility. MHC genes encode two classes of polymorphic cell-surface molecules that can recognize and bind to diverse pathogen peptides. While MHC class I genes are the classic mediators of viral-acquired immunity, larval amphibians do not express them. Consequently, MHC class II gene diversity may be an important predictor of Ranavirussusceptibility in larval amphibians, the life stage most susceptible to Ranavirus. We surveyed natural populations of larval wood frogs (Rana sylvatica), which are highly susceptible to Ranavirus, across 17 ponds and 2 years in Maryland, USA. We sequenced the peptide-binding region of an expressed MHC class IIβ locus and assessed allelic and genetic diversity. We converted alleles to functional supertypes and determined if supertypes or alleles influenced host responses to Ranavirus. Among 381 sampled individuals, 26% were infected with Ranavirus. We recovered 20 unique MHC class IIβ alleles that fell into two deeply diverged clades and seven supertypes. MHC genotypes were associated with Ranavirus infection intensity, but not prevalence. Specifically, MHC heterozygotes and supertype ST1/ST7 had significantly lower Ranavirus infection intensity compared to homozygotes and other supertypes. We conclude that MHC class IIβ functional genetic variation is an important component of Ranavirus susceptibility. Identifying immunogenetic signatures linked to variation in disease susceptibility can inform mitigation strategies for combatting global amphibian declines.



A Chinese DADA2 patient: report of two novel mutations and successful HSCT

Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by autosomal recessive mutations in Cat Eye Syndrome Chromosome Region 1 (CECR1) gene. In this report, we aimed to describe the clinical manifestations, immunological features, genotype, and treatments of one Chinese patient with novel CECR1 gene mutations. This patient initially presented with recurrent fever and rashes from the age of 3 months, but no pathogen was found. She then developed dry gangrene of the fingers at 5 months of age. Laboratory examinations revealed elevated levels of C-reactive protein and thrombocytes. The expression of interleukin-6 (IL-6) and IL-8 were both elevated. Sequencing results revealed that she had compound heterozygous mutations in CECR1 gene (c.1211T>C, p.Phe404Ser and c.1114 G>A, p.Val372Met). Subsequently, treatment with anti-IL-6 (tocilizumab) was started. However, she developed blurred vision in the right eye with occlusion of the central retinal artery, accompanied by unsteady gait. Magnetic resonance imaging (MRI) showed infarction of the right thalamus. Finally, she underwent hematopoietic stem cell transplantation (HSCT) and is currently in remission. Our findings suggest that HSCT could cure this disease.



Allelic nomenclature for the duplicated MHC class II DQ genes in sheep

Abstract

The principal MHC class II molecules involved in the presentation of peptides to the antigen specific receptors on CD4+ T cells genes in sheep are derived from DR and DQ genes. Allelic nomenclature systems for the DRB1 and its partner DRA loci are available for Ovid's; however, no official nomenclature is available for the DQ genes which creates ambiguity within the research community. Ovine MHC haplotypes include at least two pairs of DQA and DQB genes, termed DQA1DQB1 and DQA2DQB2 and both sets are polymorphic and both seem to be functional. In a number of haplotypes, the DQA1 locus appears to be absent (DQA1-null) and is replaced by a second locus termed DQA2-like. Here, we identify families of alleles based on sequence similarity and phylogenetic clustering which correspond to each of the DQA and DQB genes identified in previous genomic and transcript analyses of homozygous animals. Using such criteria to cluster sequences, we have named 82 full-length and partial cDNA transcripts derived from domestic sheep (Ovis aries) which correspond to alleles at the Ovar-DQA1DQA2DQA2-likeDQB1DQB2 and DQB2-like genes and provide associated sequence resources available to the research community through the IPD-MHC Database. This sets the basis for naming and annotation of DQ genes within the ovine MHC and may be used as a template for DQ genes in other ruminant species which will ultimately support research in livestock infectious disease.



Exploring the etiopathogenesis of systemic lupus erythematosus: a genetic perspective

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disorder that presents itself in a thousand ways. Its clinical course is extremely unpredictable, which makes diagnosis and treatment a challenge for clinicians. It appears that the clinical course of SLE is determined by genetic material in combination with environmental factors. In this article, we review recent findings on the pathogenesis of SLE from the perspective of genetics, focusing on defects in the clearance of apoptotic bodies and immune complexes, on alterations in the innate immune system response, and on impaired pathways in the adaptive immune system. Furthermore, the major histocompatibility complex (MHC) and non-MHC genes discovered during genome-wide association studies (GWASs) in SLE patients are also evaluated. In addition, the effect of these polymorphisms on the function of their related transcripts and their association with the clinical manifestations of SLE and its pathophysiology are explained. Finally, the association of genetic polymorphisms with clinical responses to common medications used in the treatment of SLE is also discussed.



Llama peripheral B-cell populations producing conventional and heavy chain-only IgG subtypes are phenotypically indistinguishable but immunogenetically distinct

Abstract

Camelid ungulates produce homodimeric heavy chain-only antibodies (HCAbs) in addition to conventional antibodies consisting of paired heavy and light chains. In the llama, HCAbs are made up by at least two subclasses (long-hinge IgG2b and short-hinge IgG2c HCAbs vs. conventional heterotetrameric IgG1s). Here, we generated murine monoclonal antibodies (mAbs) specific for the hinge-CH2 boundary of llama IgG2b (mAb 1C10) and the Fc of llama IgG2c HCAbs (mAb 5E4). Flow cytometric analysis of llama peripheral blood lymphocytes revealed that IgG1+, IgG2b+ and IgG2c+ B cells could be distinguished using mAbs 1C10/5E4 but had equivalent expression of three other cell-surface markers. MiSeq sequencing of the peripheral B cell repertoires of three llamas showed that (i) IgG2b and IgG2c HCAbs were present in similar proportions in the repertoire, (ii) a subset of IgG2b and IgG2c HCAbs, but not IgG1s, entirely lacked a hinge exon and showed direct VHH-CH2 splicing; these "hingeless" HCAbs were clonally expanded, somatically mutated and derived from hinged HCAb precursors, (iii) substantial repertoire overlap existed between IgG subclasses, especially between IgG2b and IgG2c HCAbs, (iv) the complementarity-determining region (CDR)-H3 length distributions of IgG2b and IgG2c HCAbs were broader and biased towards longer lengths compared with IgG1s due to increased N-nucleotide addition, (v) IgG2b and IgG2c HCAbs used a more restricted set of IGHV genes compared with IgG1s, and (vi) IgG2b and IgG2c HCAbs had elevated somatic mutations rates of both CDRs and framework regions (FRs) compared with IgG1s, especially of CDR-H1 and FR3. The distinct molecular features of llama IgG1, IgG2b and IgG2c antibodies imply that these subclasses may have divergent immunological functions and suggest that specific mechanisms operate to diversify HCAb repertoires in the absence of a light chain.


Improving access to cancer genetic services: perspectives of high-risk clients in a community-based setting

Abstract

Cancer genetic services are underutilized by high-risk clients in community-based health settings. To understand this disparity, 108 Planned Parenthood high-risk clients completed a utilization-focused survey. Clients expressed interest (78.8%) and intention (75.0%) in seeking genetic services. Personal/familial implications for cancer risk were the strongest motivators for seeking services (63.0–79.6%). Finances (39.6%) and worry (37.0%) were the biggest barriers. To reduce disparities in access to cancer genetics services, clinicians must understand clients' concerns and tailor their recommendations.



Health and lifestyle behaviors in colorectal cancer survivors with and without Lynch syndrome

Abstract

Lynch syndrome (LS), a hereditary cancer syndrome, accounts for approximately 3% of colorectal cancers (CRC). Positive health behaviors and surveillance are preventive strategies, but research on whether recommended behavioral guidelines are followed by individuals with LS is limited. Additional health education and promotion could be beneficial to the improved survivorship of CRC survivors. Explore health and lifestyle behaviors in CRC survivors with and without LS. We conducted a case-control study of CRC survivors with and without LS using a mailed questionnaire. Recruitment was conducted via patient registries at The University of Texas MD Anderson Cancer Center (cases n = 33; controls n = 75) and through social media (cases n = 42). CRC survivors with and without LS in our study had substantially lower smoking prevalence (5.5% and 2.7%) compared to national prevalence (18.0%). However, they had higher levels of alcohol consumption (36.8% and 10.3% for male and female LS survivors, respectively, and 35.8% and 22.0% for male and female sporadic survivors, respectively) compared to national prevalence of 13.88% for males and 6.02% for females. Both groups of CRC survivors participate in negative health behaviors that impact survivorship. More research is needed to examine the relationship between personal engagement in preventive behaviors and patient–provider relationships to improve health behaviors and explore strategies for intervention. Additionally, better health education and lifestyle change recommendations would promote and reinforce positive health outcomes in the CRC population and especially in LS survivors.



Improving follow up after predictive testing in Huntington's disease: evaluating a genetic counselling narrative group session

Abstract

Recently updated Huntington's disease (HD) predictive testing guidelines emphasise clinicians' responsibility to facilitate emotional support following testing, regardless of the result. Yet models of post-test counselling support are poorly defined. Moreover, it is unclear how these might be best delivered. In this project, a genetic counsellor and clinical psychologist developed standalone group sessions using collective narrative practices for individuals post-predictive testing. Here we present an evaluation of the experiences of one group of six people who have tested mutation positive for HD and remain pre-symptomatic. Two partners also attended the session. Observations, evaluation forms and telephone interviews were used in data collection. Interview data was available from five mutation-positive individuals and one partner. Qualitative data were analysed using a thematic framework approach. Responses were overwhelmingly positive, emphasising the importance of a specifically arranged time and space to share experiences in a structured way. This was typically the first time participants had spoken openly with someone in their situation. Narrative facilitation of discussion encouraged participants to re-discover their strengths and resiliences, with similar experiences being discovered through connections with others. The evaluation was successful in implementing group narrative interventions as part of the predictive test counselling support for Huntington's disease. Participants suggested that the approach could be extended and adopted for other genetic conditions.



Correction to: EUROCAT: an update on its functions and activities

The published online version contains the following errors: On the cover page "JRC Management Committee" – should be corrected to JRC-EUROCAT Management Committee. In the authors list under the title, same as above, "JRC Management Committee" should be corrected to JRC-EUROCAT Management Committee



Correction to: Behavioural changes, sharing behaviour and psychological responses after receiving direct-to-consumer genetic test results:a systematic review and meta-analysis

The published online version contains mistake in the Abstract section. The percentages for 'any positive lifestyle change' and 'improved dietary practices' have unintentionally been incorrectly reported.



Uncertainty related to multigene panel testing for cancer: a qualitative study on counsellors' and counselees' views

Abstract

Multigene panel testing is mainly used to improve identification of genetic causes in families with characteristics fitting multiple possible cancer syndromes. This technique may yield uncertainty, for example when variants of unknown significance are identified. This study explores counsellors' and counselees' experiences with uncertainty, and how they discuss uncertainties and decide about multigene panel testing. Six focus groups were conducted including 38 counsellors. Twelve counselees who had received genetic counselling about a multigene panel test were interviewed. The focus group sessions and interviews were audio-recorded and transcribed verbatim. Transcripts were analysed inductively by two independent coders and data were examined to obtain a comprehensive list of themes. Counsellors identified several uncertainties, e.g. finding a variant of unknown significance, or detecting an unsolicited finding. Most difficulty was experienced in deciding what uncertain information to communicate to counselees and how to do so. The extent and manner of providing uncertain information differed between centres and between counsellors. Counsellors attached more value to counselees' preferences in decision making compared to less extended tests. Counselees experienced difficulty in recalling which uncertainties had been discussed during genetic counselling. They primarily reported to have experienced uncertainty about their own and their relatives' risk of developing cancer. Counselees felt they had had a say in the decision. This study showed that counsellors need more guidance on whether and how to convey uncertainty. Undesirable practice variation in the communication of uncertainty may be prevented by determining what information should minimally be discussed to enable informed decision making.



Family health history and genetic services—the East Baltimore community stakeholder interview project

Abstract

Discussion of family health history (FH) has the potential to be a communication tool within families and with health providers to stimulate health promotion related to many chronic conditions, including those with genetic implications for prevention, screening, diagnosis, treatment. Diverse communities with disparities in health outcomes may require different approaches to engage individuals and families in the evolving areas of genetic risk communication, assessment, and services. This work was a partnership of a local urban agency and academic genetics professionals to increase understanding of community concerns and preferences related to FH and genetic awareness. Thirty community stakeholders in the East Baltimore area participated in structured interviews conducted by community members. We identified key themes on family health history FH, risk assessment, and genetic services. Forty-three percent (18/27) of community stakeholders thought families in East Baltimore did not discuss family health history FH with doctors. Stakeholders recognized the benefits and challenges of potential actions based on genetic risk assessment and the multiple competing priorities of families. FH awareness with community engagement and genetics education were the major needs identified by the participants. Research undertaken in active collaboration with community partners can provide enhanced consumer perspectives on the importance of family health history and its potential connections to health promotion and prevention activities.



Information exchange between patients with Lynch syndrome and their genetic and non-genetic health professionals: whose responsibility?

Abstract

Individuals at high risk for Lynch syndrome (LS) should be offered genetic counselling, since preventive options are available. However, uptake of genetic services and follow-up care are currently suboptimal, possibly caused by inadequate exchange of information. Therefore, this qualitative study aims to gain insight in the process of information exchange between patients diagnosed with LS and their non-genetic (i.e., general practitioner, gastroenterologist, gynaecologist) and genetic (i.e., clinical geneticist or genetic counsellor) health professionals concerning referral for genetic counselling and follow-up care. Participants comprised 13 patients diagnosed with LS (8 index patients and 5 of their affected relatives) and 24 health professionals (6 general practitioners, 8 gastroenterologists, 6 gynaecologists and 4 genetic health professionals). Analysis of the interview transcripts was performed in parallel and again after the interviews, following guidelines for qualitative research and using MAXQDA software. The main finding is that patients may 'get lost' between health professionals who lack a clear overview of their own and each other's role and responsibilities in the referral and follow-up care for patients with possible LS. Education of non-genetic health professionals and optimisation of communication between health professionals might help to enable more timely diagnosis of LS and allow patients to address their doubts and questions to the most appropriate healthcare professional.



Disclosure of diagnosis to at-risk relatives by individuals diagnosed with hypertrophic cardiomyopathy (HCM)

Abstract

Hypertrophic cardiomyopathy (HCM) affects 1 in 200 people and is the most common cause of sudden cardiac death in the young. Given that HCM usually is inherited in an autosomal dominant pattern, an HCM diagnosis has implications for biologically related family members. The purpose of this study was to explore probands' disclosure of an HCM diagnosis with these biologically related, at-risk family members. An online survey was posted on the website of the Hypertrophic Cardiomyopathy Association (HCMA), an advocacy and support group for HCM patients and their families. Descriptive statistics were used to summarize responses to closed-ended questions and demographics. Using an iterative content analysis with the constant comparison approach, we analyzed the responses to open-ended questions inquiring about the nature and role of disclosure communication with at-risk relatives. A total of 315 individuals with a self-reported diagnosis of HCM completed the survey. Most participants (98%) disclosed their diagnosis to at-risk family members. Sixty-four percent disclosed to family members less than 1 year after diagnosis. Participants also disclosed potential treatment options (74.6%) and the emotional impact of the diagnosis (39%). HCM specialists were ranked by participants as being the most helping in explaining the benefit of genetic counseling, while genetic counselor were ranked as least helpful. Emerging themes address the need to encourage screening and genetic testing among family members and to identify external educational resources for use during the disclosure process. Importantly, our study found that the process of disclosure varies based on individuals' experiences and family communication dynamics. However, almost all participants expressed the importance of disclosing the diagnosis of HCM as well as the importance of being screened and expressed needs for additional support during the disclosure process.



"A perfect society"— Swedish policymakers' ethical and social views on preconception expanded carrier screening

Abstract

To improve healthcare policymaking, commentators have recommended the use of evidence, health technology assessment, priority setting, and public engagement in the process of policymaking. Preconception expanded carrier screening, according to the World Health Organization's definition, is a novel health technology and therefore warrants assessment, part of which involves evaluating ethical and social implications. We examined ten Swedish policymakers' perspectives on ethical and social aspects of preconception expanded screening through in-depth expert interviewing, using a semi-structured questionnaire. Respondents were affiliated to governmental and non-governmental institutions that directly influence healthcare policymaking in Sweden. The interviews were recorded, transcribed verbatim, and analyzed via inductive thematic analysis method, which generated seven themes and several subthemes. Policymakers harbored concerns regarding the economics, Swedish and international political respects, implementation procedures, and societal effects, which included long-term ones. Moreover, participants detailed the role of public engagement, research, and responsibility in regard to preconception expanded carrier screening implementation. Since this is a qualitative study, with a small non-random sample, the results may not be generalizable to all policymakers in Sweden. However, the results give a profound insight into the process and interpretative knowledge of experts, in the Swedish milieu and the extent of readiness of Sweden to implement a preconception expanded carrier screening program.


Model validity for preclinical studies in precision medicine: precisely how precise do we need to be?

Abstract

The promise of personalized medicine is that each patient's treatment can be optimally tailored to their disease. In turn, their disease, as well as their response to the treatment, is determined by their genetic makeup and the "environment," which relates to their general health, medical history, personal habits, and surroundings. Developing such optimized treatment strategies is an admirable goal and success stories include examples such as switching chemotherapy agents based on a patient's tumor genotype. However, it remains a challenge to apply precision medicine to diseases for which there is no known effective treatment. Such diseases require additional research, often using experimentally tractable models. Presumably, models that recapitulate as much of the human pathophysiology as possible will be the most predictive. Here we will discuss the considerations behind such "precision models." What sort of precision is required and under what circumstances? How can the predictive validity of such models be improved? Ultimately, there is no perfect model, but our continually improving ability to genetically engineer a variety of systems allows the generation of more and more precise models. Furthermore, our steadily increasing awareness of risk alleles, genetic background effects, multifactorial disease processes, and gene by environment interactions also allows increasingly sophisticated models that better reproduce patients' conditions. In those cases where the research has progressed sufficiently far, results from these models appear to often be translating to effective treatments for patients.



Meeting report: 32nd international mammalian genome conference

Abstract

Over 150 scientists from more than 50 research institutions and eight countries attended the 32nd annual meeting of the International Mammalian Genome Society (IMGS) held in Rio Mar, Puerto Rico. Attendees included predoctoral and postdoctoral trainees, junior investigators, clinicians, industry professionals, and established leaders in mammalian genetics and genomics. From November 11–14, major scientific advances in the fields of systems genetics, developmental biology, cancer, human disease modeling, and bioinformatics were showcased in a series of 66 poster and 54 platform presentations. Here we provide an overview of the meeting's proceedings and summarize the exciting, novel research findings communicated by conference participants that, collectively, are advancing the frontiers of mammalian genetics and genomics.



Analysis and preliminary validation of the molecular mechanism of fat deposition in fatty and lean pigs by high-throughput sequencing

Abstract

Fat deposition in muscle includes intramuscular fat (IMF) and intermuscular fat. IMF content is an index of pork quality; however, because IMF content is difficult to measure in vivo in young animals, conventional breeding for IMF content is difficult to carry out. The mechanism and progression of animal fat deposition is not well understood, and there are currently no effective control methods. In this study, using Laiwu and large white pigs as the research subjects and RNA sequencing technology, we analyzed the genetic mechanism of animal fat deposition in pigs. Specifically, we analyzed the features of lncRNAs and their potential target genes. We obtained 464 million clean reads, from which 907 lncRNAs were identified. The cis and trans analysis identified target genes, including genes that were upregulated (286) and downregulated (621) in the fatty and lean pigs. ENSSSCG00000008692_ADD1, ENSSSCG00000023124_ADD1 and ENSSSCG00000005918_DGAT1 were validated as target genes of the lncRNAs and were shown to be closely related to fat deposition. These results provide a basis for studying the different metabolic lncRNA expression of IMF deposition. In addition, as the valuable model animal to study the mechanisms of obesity, pigs may represent a new avenue for studying human obesity.



The guanine nucleotide exchange factor, Spata13 , influences social behaviour and nocturnal activity

Abstract

Spermatogenesis-associated protein 13 (Spata13) is a guanine nucleotide exchange factor (GEF) enriched in discrete brain regions in the adult, with pronounced expression in the extended central amygdala (CeA). Loss of Spata13, also known as the adenomatous polyposis coli exchange factor Asef2, has no identifiable phenotype although it has been shown to reduce the number and size of intestinal tumours in Apc (Min/+) mice. Nevertheless, its brain-related functions have not been investigated. To pursue this, we have generated a Spata13 knockout mouse line using CRISPR-mediated deletion of an exon containing the GTPase domain that is common to multiple isoforms. Homozygous mutants were viable and appeared normal. We subjected both male and female cohorts to a comprehensive battery of behavioural tests designed to investigate particular CeA-related functions. Here, we show that Spata13 modulates social behaviour with homozygous mutants being subordinate to wildtype controls. Furthermore, female homozygotes show increased activity in home cages during the dark phase of the light–dark cycle. In summary, Spata13 modulates social hierarchy in both male and female mice in addition to affecting voluntary activity in females.



Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves

Abstract

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I (COL1A1), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it was absent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.



A high-density genetic map and molecular sex-typing assay for gerbils

Abstract

We constructed a high-density genetic map for Mongolian gerbils (Meriones unguiculatus). We genotyped 137 F2 individuals with a genotype-by-sequencing (GBS) approach at over 10,000 loci and built the genetic map using a two-step approach. First, we chose the highest-quality set of 485 markers to construct a robust map of 1239 cM with 22 linkage groups as expected from the published karyotype. Second, we added an additional 5449 markers onto the map based on their genotype similarity with the original markers. We used the final marker set to assemble 1140 genomic scaffolds (containing ~ 20% of annotated genes) into a chromosome-level assembly. We used both genetic linkage and relative sequencing coverage in males and females to identify X- and Y-chromosome scaffolds and from these we designed a robust and internally-controlled PCR assay to determine sex. This assay will facilitate early stage sex-typing of embryonic and young gerbils which is difficult using current visual methods. Accession ID: Meriones unguiculatus: 10047.



Humanized mouse models of immunological diseases and precision medicine

Abstract

With the increase in knowledge resulting from the sequencing of the human genome, the genetic basis for the underlying differences in individuals, their diseases, and how they respond to therapies is starting to be understood. This has formed the foundation for the era of precision medicine in many human diseases that is beginning to be implemented in the clinic, particularly in cancer. However, preclinical testing of therapeutic approaches based on individual biology will need to be validated in animal models prior to translation into patients. Although animal models, particularly murine models, have provided significant information on the basic biology underlying immune responses in various diseases and the response to therapy, murine and human immune systems differ markedly. These fundamental differences may be the underlying reason why many of the positive therapeutic responses observed in mice have not translated directly into the clinic. There is a critical need for preclinical animal models in which human immune responses can be investigated. For this, many investigators are using humanized mice, i.e., immunodeficient mice engrafted with functional human cells, tissues, and immune systems. We will briefly review the history of humanized mice, the remaining limitations, approaches to overcome them and how humanized mouse models are being used as a preclinical bridge in precision medicine for evaluation of human therapies prior to their implementation in the clinic.



Treating Rett syndrome: from mouse models to human therapies

Abstract

Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Mecp2-mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.



Correction to: Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

The original article has been published with an incorrect text in Materials and Methods section. The corrected text should read as.



Fearful old world? A commentary on the Second International Summit on human genome editing

Abstract

Genome editing is revolutionising our ability to modify genomes with exquisite precision for medical and agricultural applications, and in basic research. The first International Summit on Human Genome Editing, organised jointly by the US National Academies of Sciences and Medicine, the Chinese Academy of Sciences and the UK Royal Society, was held in Washington DC at the end of 2015. Its aim was to explore scientific, legal and ethical perspectives on the prospective use of human genome editing as a therapeutic intervention in disease (so-called somatic genome editing) and as a possible intervention in human reproduction (so-called germ-line genome editing). Following that Summit, the Organising Committee had, in a press release, come to the conclusion that: "It would be irresponsible to proceed with any clinical use of germ line editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application" (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a). A report from the US National Academies subsequently reiterated and developed the approach.



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