Analysis of Haplotype Structure in the Bovine Major Histocompatibility Complex

The goal of this project was to identify and characterize polymorphic markers spanning regions of the bovine major histocompatibility complex (BoLA) to analyze patterns of genetic variation and haplotype structure across diverse cattle breeds with various breed histories and selection pressures. Genetic markers that demonstrated sufficient levels of polymorphism, locus specificity, Mendelian inheritance, and the accurate typing of alleles across diverse haplotypes were chosen to define separate haplotype structures for the BoLA IIb and BoLA IIa-III-I regions and to evaluate breakpoints in linkage disequilibrium within the regions surrounding BoLA IIa-III-I. A total of 23 microsatellites, two SNPSTRs, 62 SNPs, and the alleles of three class IIa genes were selected for use in this study. These markers revealed eleven recombination events, low levels of recombination in BoLA IIa-III-I, a sharp break in haplotype structure in the region centromeric to class IIa, prolonged linkage disequilibrium in the extended class I region, strong conservation of BoLA IIa-III-I haplotype structure, BoLA IIa-III-I homozygous haplotype identity across seven different breeds of cattle, and a small number of common BoLA IIa-III-I haplotypes within the Angus and Holstein breeds. This work demonstrated that 52 SNPs from the Illumina 50K SNPchip could accurately predict BoLA IIa-III-I haplotypes. These 52 SNPs represent tagSNPs that can predict BoLA IIa-III-I genetic variation and could offer a cost-effective means for screening large sample sizes for haplotype/disease association studies in the future

Analysis of Haplotype Structure in the Bovine Major Histocompatibility Complex

The goal of this project was to identify and characterize polymorphic markers spanning regions of the bovine major histocompatibility complex (BoLA) to analyze patterns of genetic variation and haplotype structure across diverse cattle breeds with various breed histories and selection pressures. Genetic markers that demonstrated sufficient levels of polymorphism, locus specificity, Mendelian inheritance, and the accurate typing of alleles across diverse haplotypes were chosen to define separate haplotype structures for the BoLA IIb and BoLA IIa-III-I regions and to evaluate breakpoints in linkage disequilibrium within the regions surrounding BoLA IIa-III-I. A total of 23 microsatellites, two SNPSTRs, 62 SNPs, and the alleles of three class IIa genes were selected for use in this study. These markers revealed eleven recombination events, low levels of recombination in BoLA IIa-III-I, a sharp break in haplotype structure in the region centromeric to class IIa, prolonged linkage disequilibrium in the extended class I region, strong conservation of BoLA IIa-III-I haplotype structure, BoLA IIa-III-I homozygous haplotype identity across seven different breeds of cattle, and a small number of common BoLA IIa-III-I haplotypes within the Angus and Holstein breeds. This work demonstrated that 52 SNPs from the Illumina 50K SNPchip could accurately predict BoLA IIa-III-I haplotypes. These 52 SNPs represent tagSNPs that can predict BoLA IIa-III-I genetic variation and could offer a cost-effective means for screening large sample sizes for haplotype/disease association studies in the future

A high resolution RH map of the bovine major histocompatibility complex

<p>Abstract</p> <p>Background</p> <p>The cattle MHC is termed the bovine leukocyte antigen (BoLA) and, along with the MHCs of other ruminants, is unique in its genomic organization. Consequently, correct and reliable gene maps and sequence information are critical to the study of the BoLA region. The bovine genome sequencing project has produced two assemblies (Btau_3.1 and 4.0) that differ substantially from each other and from conventional gene maps in the BoLA region. To independently compare the accuracies of the different sequence assemblies, we have generated a high resolution map of BoLA using a 12,000_radradiation hybrid panel. Seventy-seven unique sequence tagged site (STS) markers chosen at approximately 50 kb intervals from the Btau 2.0 assembly and spanning the IIa-III-I and IIb regions of the bovine MHC were mapped on a 12,000_radbovine radiation hybrid (RH) panel to evaluate the different assemblies of the bovine genome sequence.</p> <p>Results</p> <p>Analysis of the data generated a high resolution RH map of BoLA that was significantly different from the Btau_3.1 assembly of the bovine genome but in good agreement with the Btau_4.0 assembly. Of the few discordancies between the RH map and Btau_4.0, most could be attributed to closely spaced markers that could not be precisely ordered in the RH panel. One probable incorrectly-assembled sequence and three missing sequences were noted in the Btau_4.0 assembly. The RH map of BoLA is also highly concordant with the sequence-based map of HLA (NCBI build 36) when reordered to account for the ancestral inversion in the ruminant MHC.</p> <p>Conclusion</p> <p>These results strongly suggest that studies using Btau_3.1 for analyses of the BoLA region should be reevaluated in light of the Btau_4.0 assembly and indicate that additional research is needed to produce a complete assembly of the BoLA genomic sequences.</p

Personality profiles of cultures: aggregate personality traits

Personality profiles of cultures can be operationalized as the mean trait levels of culture members. College students from 51 cultures rated an individual from their country whom they knew well (N = 12, 156). Aggregate scores on Revised NEO Personality Inventory scales generalized across age and gender groups, approximated the individual-level Five-Factor Model, and correlated with aggregate self-report personality scores and other culture-level variables. Results were not attributable to national differences in economic development or to acquiescence. Geographical differences in scale variances and mean levels were replicated, with Europeans and Americans generally scoring higher in Extraversion than Asians and Africans. Findings support the rough scalar equivalence of NEO-PI-R factors and facets across cultures, and suggest that aggregate personality profiles provide insight into cultural differences

Genome-Wide Association Study Implicates Testis-Sperm Specific <em>FKBP6</em> as a Susceptibility Locus for Impaired Acrosome Reaction in Stallions

<div><p>Impaired acrosomal reaction (IAR) of sperm causes male subfertility in humans and animals. Despite compelling evidence about the genetic control over acrosome biogenesis and function, the genomics of IAR is as yet poorly understood, providing no molecular tools for diagnostics. Here we conducted Equine SNP50 Beadchip genotyping and GWAS using 7 IAR–affected and 37 control Thoroughbred stallions. A significant (<em>P</em><6.75E-08) genotype–phenotype association was found in horse chromosome 13 in FK506 binding protein 6 (<em>FKBP6</em>). The gene belongs to the immunophilins FKBP family known to be involved in meiosis, calcium homeostasis, clathrin-coated vesicles, and membrane fusions. Direct sequencing of <em>FKBP6</em> exons in cases and controls identified SNPs g.11040315G>A and g.11040379C>A (p.166H>N) in exon 4 that were significantly associated with the IAR phenotype both in the GWAS cohort (n = 44) and in a large multi-breed cohort of 265 horses. All IAR stallions were homozygous for the A-alleles, while this genotype was found only in 2% of controls. The equine <em>FKBP6</em> was exclusively expressed in testis and sperm and had 5 different transcripts, of which 4 were novel. The expression of this gene in AC/AG heterozygous controls was monoallelic, and we observed a tendency for <em>FKBP6</em> up-regulation in IAR stallions compared to controls. Because exon 4 SNPs had no effect on the protein structure, it is likely that <em>FKBP6</em> relates to the IAR phenotype via regulatory or modifying functions. In conclusion, <em>FKBP6</em> was considered a susceptibility gene of incomplete penetrance for IAR in stallions and a candidate gene for male subfertility in mammals. <em>FKBP6</em> genotyping is recommended for the detection of IAR–susceptible individuals among potential breeding stallions. Successful use of sperm as a source of DNA and RNA propagates non-invasive sample procurement for fertility genomics in animals and humans.</p> </div

Inbreeding coefficients (diagonal boxes) and genetic relationship coefficients of and among the seven affected stallions calculated from i) pedigree data in bold (upper triangle of the matrix) and from ii) SNP genotyping data in normal font (lower triangle of the matrix).

<p>Stallion code names correspond to the codes in the 5-generation pedigree (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003139#pgen.1003139.s001" target="_blank">Figure S1</a>).</p>*<p>The diagonal boxes in <b><i>bold italics with %</i></b> that should correspond to self-to-self genetic relationship ( = 1) have been used to show inbreeding coefficients for each of the 7 stallions.</p

Schematic of the IAR–associated region in ECA13p.

<p>(A) A G-banded ideogram of ECA13 (ISCNH, 1997) showing the cytogenetic location of the IAR associated region; (B) Statistical significance values for 721 ECA13 SNPs analyzed for genome wide association using chi-square; yellow shade highlights the IAR-associated ∼3.9 Mb region; (C) Sequence map of chr13:8,000,000–11,900,000 showing all ENSMBL annotated genes in the region; <i>TRIM56</i> and <i>FKBP6</i> are highlighted. (D) A graph showing chi-square test −log₁₀(<i>P</i>) values for 10 significant SNPs: 1–8027172, 2–8382955, 3–8977804, 4–8987922, 5–9034435, 6–9034502, 7–9183989, 8–10894213, 9–11043916 (black circles), and 10–11044175 (red circle); the seven SNPs above the grey line showed moderate significance also in mixed model; (E) Confidence interval LD blocks; (F) Solid spine LD blocks; blocks with significant permuted <i>P</i>-values (<i>P</i><0.0005) for association with IAR are highlighted yellow; red diamonds represent D′ values equal to 1, lower values of D′ are presented in blue and white; the ∼306 kb highly associated haplotype in both LD analyses is in a red box.</p

<i>FKBP6</i> exon 4 genotype frequencies across horse breeds: Thoroughbred, TB (n = 145); Quarter Horse, QH (n = 56); other breeds (21 breeds; n = 64; 1 to 8 individuals each).

<p>The IAR susceptibility genotype AAAA is in bold italics.</p