Transcriptional profiling of Ovis aries identifies Ovar-DQA1 allele frequency differences between nematode-resistant and susceptible selection lines

Gastrointestinal nematodes are a major cause of disease in grazing livestock; however, individual animals differ in their response to infection. To identify genes whose expression correlates with resistance status, transcriptional profiling of resistant and susceptible sheep was undertaken. Transcription profiles were taken at three time points during the growth of lambs. The number of genes differentially expressed increased as animals were exposed to longer nematode challenge. Almost 300 genes, with a variety of functions, were differentially expressed overall, although genes more highly expressed in resistant animals typically had major histocompatibility complex (MHC) II, free radical scavenging or smooth muscle-specific functions. The Ovar-DQA1 gene was 8.4-fold more highly expressed in resistant animals. This was due in part to a higher frequency of DQA1 null alleles in susceptible animals. The null allele of DQA1 was also associated with susceptibility in a separate selection flock, presenting the hypothesis that failure to present parasite antigens to immune cells led to nematode susceptibility. To test this hypothesis, commercial rams from three breeds were genotyped for the null allele of DQA1. The homozygous null allele was associated with susceptibility in only one of the three breeds tested indicating that the null allele does not cause susceptibility to intestinal parasites per se but is probably in linkage disequilibrium with additional polymorphisms in the MHC region. A combination of these polymorphisms may contribute to susceptibility in some populations. The extent of linkage disequilibrium between polymorphisms may vary from breed to breed or population to population.

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Association analysis and functional annotation of imputed sequence data within genomic regions influencing resistance to gastro-intestinal parasites detected by an LDLA approach in a nucleus flock of Sarda dairy sheep

Genetics Selection Evolution ◽

10.1186/s12711-021-00690-7 ◽

2022 ◽

Vol 54 (1) ◽

Author(s):

Sara Casu ◽

Mario Graziano Usai ◽

Tiziana Sechi ◽

Sotero L. Salaris ◽

Sabrina Miari ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Candidate Genes ◽

Association Analysis ◽

Functional Annotation ◽

Sequence Data ◽

Ovis Aries ◽

Differentially Expressed ◽

Phenotypic Variance ◽

Major Health Problem ◽

Functional Variants

Abstract Background Gastroinestinal nematodes (GIN) are one of the major health problem in grazing sheep. Although genetic variability of the resistance to GIN has been documented, traditional selection is hampered by the difficulty of recording phenotypes, usually fecal egg count (FEC). To identify causative mutations or markers in linkage disequilibrium (LD) to be used for selection, the detection of quantitative trait loci (QTL) for FEC based on linkage disequilibrium-linkage analysis (LDLA) was performed on 4097 ewes (from 181 sires) all genotyped with the OvineSNP50 Beadchip. Identified QTL regions (QTLR) were imputed from whole-genome sequences of 56 target animals of the population. An association analysis and a functional annotation of imputed polymorphisms in the identified QTLR were performed to pinpoint functional variants with potential impact on candidate genes identified from ontological classification or differentially expressed in previous studies. Results After clustering close significant locations, ten QTLR were defined on nine Ovis aries chromosomes (OAR) by LDLA. The ratio between the ANOVA estimators of the QTL variance and the total phenotypic variance ranged from 0.0087 to 0.0176. QTL on OAR4, 12, 19, and 20 were the most significant. The combination of association analysis and functional annotation of sequence data did not highlight any putative causative mutations. None of the most significant SNPs showed a functional effect on genes’ transcript. However, in the most significant QTLR, we identified genes that contained polymorphisms with a high or moderate impact, were differentially expressed in previous studies, contributed to enrich the most represented GO process (regulation of immune system process, defense response). Among these, the most likely candidate genes were: TNFRSF1B and SELE on OAR12, IL5RA on OAR19, IL17A, IL17F, TRIM26, TRIM38, TNFRSF21, LOC101118999, VEGFA, and TNF on OAR20. Conclusions This study performed on a large experimental population provides a list of candidate genes and polymorphisms which could be used in further validation studies. The expected advancements in the quality of the annotation of the ovine genome and the use of experimental designs based on sequence data and phenotypes from multiple breeds that show different LD extents and gametic phases may help to identify causative mutations.

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Transcriptional profiling of differentially expressed long non-coding RNAs in breast cancer

Genomics Data ◽

10.1016/j.gdata.2015.09.020 ◽

2015 ◽

Vol 6 ◽

pp. 214-216 ◽

Cited By ~ 1

Author(s):

Lizhen Wang ◽

Xiaokun Shen ◽

Bojian Xie ◽

Zhaosheng Ma ◽

Xiaobing Chen ◽

...

Keyword(s):

Breast Cancer ◽

Transcriptional Profiling ◽

Differentially Expressed ◽

Non Coding Rnas

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Abstract 12291: Contribution of Rare Mutations in Mendelian Hypercholesterolemia Genes to Risk for Premature Coronary Artery Disease in the Population

Circulation ◽

10.1161/circ.130.suppl_2.12291 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Hong-Hee Won ◽

Ron Do ◽

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Null Allele ◽

Coronary Revascularization ◽

Null Alleles ◽

Premature Coronary Artery Disease ◽

Rare Mutations ◽

Increased Risk ◽

Artery Disease ◽

Cad Risk

Introduction: Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for coronary artery disease (CAD). Rare mutations in at least 6 genes lead to Mendelian forms of high or reduced LDL-C; three ( APOB, LDLR, PCSK9 ) act in a dominant pattern whereas three ( ABCG5, ABCG8, LDLRAP1 ) in a recessive pattern. We address to what extent rare mutations in Mendelian LDL-C genes contribute to early CAD risk in the population. Methods: We sequenced the exons of the 6 genes in 9,329 early CAD cases (myocardial infarction, angiographic CAD, or coronary revascularization in men≤50 and women≤60) and 10,245 controls from 9 studies using targeted and whole exome next-generation sequencing. We tested 3 sets: ‘Null alleles’ (nonsense, splice-site, or frameshift); ‘Deleterious (7/7)’ (null and missense annotated as damaging by 7 algorithms); and ‘Deleterious (6/7)’ (null and missense annotated as damaging by at least 6 algorithms). Given the rarity of deleterious mutations, we aggregated these mutations in each gene and tested for an excess or deficit in cases vs . controls. Results: Counts of mutations are provided in Table. Null mutations in LDLR , carried by 1:500 participants, confered a 8-fold increase in CAD risk (P=8х10 -7 ) whereas heterozygosity for a null mutation in ABCG5 (1:650 frequency) was associated with a 3-fold increased risk (P=5х10 -3 ). ‘Deleterious (7/7)’ mutations in LDLR , carried by 1:100 participants, confered a 4-fold increased risk (P=8х10 -17 ) whereas heterozygosity for a ‘Deleterious (7/7)’ mutation in ABCG5 (1:250 frequency) was associated with a 2-fold increased risk (P=2х10 -3 ). Heterozygous null allele carriers at LDLR and ABCG5 had increased LDL-C (P<0.001). Conclusions: Of early CAD cases, 2-3% carry a rare, deleterious mutation at LDLR or ABCG5 associated with increased risk. Although previously reported to cause recessive sitosterolemia, we find that heterozygosity for a null allele at ABCG5 is associated with markedly higher early CAD risk.

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Abstract 495: GSTM1 Deficiency Exacerbates Hypertension in the Remnant Model of Chronic Kidney Disease

Hypertension ◽

10.1161/hyp.62.suppl_1.a495 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Sylvia Cechova ◽

Rosa Chan ◽

Beverly Koller ◽

Thu H Le

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Null Allele ◽

Null Alleles ◽

Hypertensive Nephrosclerosis ◽

Baseline Systolic Blood Pressure ◽

Glutathione S Transferases ◽

Targeting Strategy ◽

Multiple Chronic Diseases

There is a general consensus that oxidative stress is a factor in the progression of chronic kidney disease (CKD). Hence, genetic variants that affect the capacity to handle oxidative stress may influence the outcomes of CKD. One important class of enzymes that has evolved to combat the damaging effects of reactive oxygen species is the glutathione-S-transferases. In particular, the μ class isoform 1 (GSTM1) has emerged as a potential modifier of multiple chronic diseases in humans. Approximately 30%-50% of humans are completely deficient of the GSTM1 enzyme because of homozygous inheritance of the GSTM1 null allele, GSTM1(0). We have identified the GSTM1 gene as a modifier of disease progression in hypertensive nephrosclerosis (HN). In an ancillary study of the African American (AA) Study of Hypertension and Kidney Disease (AASK) Trial, we reported that participants carrying one ( 1/0 ) or two ( 0/0 ) null alleles had 1.7- and 2-fold higher risk of the composite outcome of a 50% decline in the glomerular filtration rate (GFR), dialysis, or death relative to those with two active alleles. Here, the objective of our study was to determine the consequence of deletion of Gstm1 on the course of chronic kidney disease induced by reduction of renal mass (RRM) model in mice. We generated Gstm1-/- (KO) mice on the 129S6 background through conventional gene targeting strategy. By radiotelemetry, Gstm1 KO mice displayed a modest but significantly higher baseline systolic blood pressure (SBP) compared to their wild type (WT, Gtsm1 +/+ ) littermates: KO (n = 5): 138.8 ± 1.3; WT (n = 5): 132.1 ± 1.1, p < 0.01. Baseline urinary isoprostane (ng/100 mg of body weight) was significantly higher in KO mice than WT mice (15.1 ± 2.9; WT: 8.0 ± 0.8, p < 0.04). Four weeks after sub-total nephrectomy, Gstm1 KO mice developed significantly more severe hypertension than WT mice. The average SBP over a 2 week recording by radiotelemetry was 154.0 ± 3.2 mm Hg in KO mice (n = 5), and 142.3 ± 4.2 in WT mice (n = 3), p < 0.01. The effects of deletion of Gstm1 on kidney function and histopathology are under investigation. In conclusion, loss of GSMT1 increases oxidative stress and exaggerates hypertension in the murine model of chronic kidney disease.

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Phytophthora infestans Sporangia Produced in Culture and on Tomato Leaflet Lesions Show Marked Differences in Indirect Germination Rates, Aggressiveness, and Global Transcription Profiles

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-09-18-0255-ta ◽

2019 ◽

Vol 32 (5) ◽

pp. 515-526 ◽

Cited By ~ 5

Author(s):

William E. Fry ◽

Sean P. Patev ◽

Kevin L. Myers ◽

Kan Bao ◽

Zhangjun Fei

Keyword(s):

Phytophthora Infestans ◽

Differentially Expressed Genes ◽

Differentially Expressed ◽

Rna Seq ◽

Moist Chamber ◽

Field Isolates ◽

Rxlr Effectors ◽

Transcription Profiles ◽

Independent Field ◽

Pure Cultures

Sporangia of Phytophthora infestans from pure cultures on agar plates are typically used in lab studies, whereas sporangia from leaflet lesions drive natural infections and epidemics. Multiple assays were performed to determine if sporangia from these two sources are equivalent. Sporangia from plate cultures showed much lower rates of indirect germination and produced much less disease in field and moist-chamber tests. This difference in aggressiveness was observed whether the sporangia had been previously incubated at 4°C (to induce indirect germination) or at 21°C (to prevent indirect germination). Furthermore, lesions caused by sporangia from plates produced much less sporulation. RNA-Seq analysis revealed that thousands of the >17,000 P. infestans genes with a RPKM (reads per kilobase of exon model per million mapped reads) >1 were differentially expressed in sporangia obtained from plate cultures of two independent field isolates compared with sporangia of those isolates from leaflet lesions. Among the significant differentially expressed genes (DEGs), putative RxLR effectors were overrepresented, with almost half of the 355 effectors with RPKM >1 being up- or downregulated. DEGs of both isolates include nine flagellar-associated genes, and all were down-regulated in plate sporangia. Ten elicitin genes were also detected as DEGs in both isolates, and nine (including INF1) were up-regulated in plate sporangia. These results corroborate previous observations that sporangia produced from plates and leaflets sometimes yield different experimental results and suggest hypotheses for potential mechanisms. We caution that use of plate sporangia in assays may not always produce results reflective of natural infections and epidemics.

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Molecular genetics of cryptopleurine resistance in Saccharomyces cerevisiae: expression of a ribosomal protein gene family.

Genetics ◽

10.1093/genetics/135.3.719 ◽

1993 ◽

Vol 135 (3) ◽

pp. 719-730

Author(s):

A G Paulovich ◽

J R Thompson ◽

J C Larkin ◽

Z Li ◽

J L Woolford

Keyword(s):

Saccharomyces Cerevisiae ◽

Ribosomal Protein ◽

Gene Fusion ◽

Null Allele ◽

Ribosomal Subunit ◽

Null Alleles ◽

Protein Synthesis Inhibitor ◽

Lacz Gene ◽

Ribosomal Subunits ◽

Cry1 Gene

Abstract The Saccharomyces cerevisiae CRY1 gene encodes the 40S ribosomal subunit protein rp59 and confers sensitivity to the protein synthesis inhibitor cryptopleurine. A yeast strain containing the cry1-delta 1::URA3 null allele is viable, cryptopleurine sensitive (CryS), and expresses rp59 mRNA, suggesting that there is a second functional CRY gene. The CRY2 gene has been isolated from a yeast genomic library cloned in bacteriophage lambda, using a CRY1 DNA probe. The DNA sequence of the CRY2 gene contains an open reading frame encoding ribosomal protein 59 that differs at five residues from rp59 encoded by the CRY1 gene. The CRY2 gene was mapped to the left arm of chromosome X, centromere-proximal to cdc6 and immediately adjacent to ribosomal protein genes RPS24A and RPL46. Ribosomal protein 59 is an essential protein; upon sporulation of a diploid doubly heterozygous for cry1-delta 2::TRP1 cry2-delta 1::LEU2 null alleles, no spore clones containing both null alleles were recovered. Several results indicate that CRY2 is expressed, but at lower levels than CRY1: (1) Introduction of CRY2 on high copy plasmids into CryR yeast of genotype cry1 CRY2 confers a CryS phenotype. Transformation of these CryR yeast with CRY2 on a low copy CEN plasmid does not confer a CryS phenotype. (2) Haploids containing the cry1-delta 2::TRP1 null allele have a deficit of 40S ribosomal subunits, but cry2-delta 1::LEU2 strains have wild-type amounts of 40S ribosomal subunits. (3) CRY2 mRNA is present at lower levels than CRY1 mRNA. (4) Higher levels of beta-galactosidase are expressed from a CRY1-lacZ gene fusion than from a CRY2-lacZ gene fusion. Mutations that alter or eliminate the last amino acid of rp59 encoded by either CRY1 or CRY2 result in resistance to cryptopleurine. Because CRY2 (and cry2) is expressed at lower levels than CRY1 (and cry1), the CryR phenotype of cry2 mutants is only expressed in strains containing a cry1-delta null allele.

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Expression of Functional CD32 Molecules on Human NK Cells Is Determined by an Allelic Polymorphism of the FcγRIIC Gene

Blood ◽

10.1182/blood.v91.7.2369.2369_2369_2380 ◽

1998 ◽

Vol 91 (7) ◽

pp. 2369-2380 ◽

Cited By ~ 2

Author(s):

Diana Metes ◽

Linda K. Ernst ◽

William H. Chambers ◽

Andrei Sulica ◽

Ronald B. Herberman ◽

...

Keyword(s):

Nk Cells ◽

Null Allele ◽

Nk Cell ◽

Full Length ◽

Null Alleles ◽

Soluble Form ◽

Allelic Polymorphism ◽

Reading Frame ◽

Normal Individuals ◽

Alternatively Spliced

Human natural killer (NK) cells were thought to express only FcγRIIIA (CD16), but recent reports have indicated that NK cells also express a second type of FcγR, ie, FcγRII (CD32). We have isolated, cloned, and sequenced full-length cDNAs of FcγRII from NK cells derived from several normal individuals that may represent four different products of the FcγRIIC gene. One transcript (IIc1) is identical with the already described FcγRIIc form. The other three (IIc2-IIc4) appear to represent unique, alternatively spliced products of the same gene, and include a possible soluble form. Analyses of the full-length clones have revealed an allelic polymorphism in the first extracellular exon, resulting in either a functional open reading frame isoform or a null allele. Stable transfection experiments enabled us to determine a unique binding pattern of anti-CD32 monoclonal antibodies to FcγRIIc. Further analyses of NK-cell preparations revealed heterogeneity in CD32 expression, ranging from donors lacking CD32 expression to donors expressing high levels of CD32 that were capable of triggering cytotoxicity. Differences in expression were correlated with the presence or absence of null alleles. These data show that certain individuals express high levels of functional FcγRIIc isoforms on their NK cells.

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The calculation of recombination frequencies in crosses of allogamous plant species with applications to linkage mapping

Genetics Research ◽

10.1017/s0016672300033474 ◽

1996 ◽

Vol 67 (1) ◽

pp. 55-65 ◽

Cited By ~ 34

Author(s):

E. Ritter ◽

F. Salamini

Keyword(s):

Linkage Mapping ◽

Null Allele ◽

Null Alleles ◽

Marker Allele ◽

Information Functions ◽

Original Proposal ◽

Point Estimates ◽

Allelic Configuration ◽

Single Marker ◽

Marker Class

SummaryThe recombination frequency (r) between two loci defined by conventional or molecular markers can be estimated by solving proper Maximum Likelihood equations. These are based on expected and observed marker class frequencies in the progeny of a cross, and are specific for each allelic configuration of the parents(1). In a cross between two diploid parents up to four different alleles, besides a null allele, can be detected at one locus. This defines in each parent, considering a locus A, nine basic allelic configurations based on two allelic marker fragments(Ai/Aj), one single marker allele and a null allele (Ai/AO), or just null alleles (AO/AO). With respect to two loci the consideration of all possible diploid allelic configurations in the parents of a cross allows the detection of 21 different expected marker class distributions producing estimates of r in the progeny. General formulas for calculating the ML equations and the corresponding information functions have been developed for the 21 marker class distributions. Simplified formulas have been also derived and the relative efficiency of the information functions compared. As expected, in the majority of cases, allelic marker configurations give more precise estimates of linkage values than single marker configurations. A method for the construction of linkage maps based on two point estimates, linkage subgroups and allelic bridges is presented. The method is an improvementon an original proposal by Ritter et al.(1990).

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