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1.  Assessment of autozygosity in Nellore cows (Bos indicus) through high-density SNP genotypes 
The use of relatively low numbers of sires in cattle breeding programs, particularly on those for carcass and weight traits in Nellore beef cattle (Bos indicus) in Brazil, has always raised concerns about inbreeding, which affects conservation of genetic resources and sustainability of this breed. Here, we investigated the distribution of autozygosity levels based on runs of homozygosity (ROH) in a sample of 1,278 Nellore cows, genotyped for over 777,000 SNPs. We found ROH segments larger than 10 Mb in over 70% of the samples, representing signatures most likely related to the recent massive use of few sires. However, the average genome coverage by ROH (>1 Mb) was lower than previously reported for other cattle breeds (4.58%). In spite of 99.98% of the SNPs being included within a ROH in at least one individual, only 19.37% of the markers were encompassed by common ROH, suggesting that the ongoing selection for weight, carcass and reproductive traits in this population is too recent to have produced selection signatures in the form of ROH. Three short-range highly prevalent ROH autosomal hotspots (occurring in over 50% of the samples) were observed, indicating candidate regions most likely under selection since before the foundation of Brazilian Nellore cattle. The putative signatures of selection on chromosomes 4, 7, and 12 may be involved in resistance to infectious diseases and fertility, and should be subject of future investigation.
doi:10.3389/fgene.2015.00005
PMCID: PMC4310349
Bos indicus; runs of homozygosity; selection; cattle; fertility; disease resistance
2.  Accuracy of genotype imputation in Nelore cattle 
Background
Genotype imputation from low-density (LD) to high-density single nucleotide polymorphism (SNP) chips is an important step before applying genomic selection, since denser chips tend to provide more reliable genomic predictions. Imputation methods rely partially on linkage disequilibrium between markers to infer unobserved genotypes. Bos indicus cattle (e.g. Nelore breed) are characterized, in general, by lower levels of linkage disequilibrium between genetic markers at short distances, compared to taurine breeds. Thus, it is important to evaluate the accuracy of imputation to better define which imputation method and chip are most appropriate for genomic applications in indicine breeds.
Methods
Accuracy of genotype imputation in Nelore cattle was evaluated using different LD chips, imputation software and sets of animals. Twelve commercial and customized LD chips with densities ranging from 7 K to 75 K were tested. Customized LD chips were virtually designed taking into account minor allele frequency, linkage disequilibrium and distance between markers. Software programs FImpute and BEAGLE were applied to impute genotypes. From 995 bulls and 1247 cows that were genotyped with the Illumina® BovineHD chip (HD), 793 sires composed the reference set, and the remaining 202 younger sires and all the cows composed two separate validation sets for which genotypes were masked except for the SNPs of the LD chip that were to be tested.
Results
Imputation accuracy increased with the SNP density of the LD chip. However, the gain in accuracy with LD chips with more than 15 K SNPs was relatively small because accuracy was already high at this density. Commercial and customized LD chips with equivalent densities presented similar results. FImpute outperformed BEAGLE for all LD chips and validation sets. Regardless of the imputation software used, accuracy tended to increase as the relatedness between imputed and reference animals increased, especially for the 7 K chip.
Conclusions
If the Illumina® BovineHD is considered as the target chip for genomic applications in the Nelore breed, cost-effectiveness can be improved by genotyping part of the animals with a chip containing around 15 K useful SNPs and imputing their high-density missing genotypes with FImpute.
Electronic supplementary material
The online version of this article (doi:10.1186/s12711-014-0069-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12711-014-0069-1
PMCID: PMC4192291
3.  Corrigendum: Evaluation of the lasso and the elastic net in genome-wide association studies 
Frontiers in Genetics  2014;5:349.
doi:10.3389/fgene.2014.00349
PMCID: PMC4181229
LASSO; elastic net; simulation; GWAS; population structure; cattle
4.  Assessing signatures of selection through variation in linkage disequilibrium between taurine and indicine cattle 
Background
Signatures of selection are regions in the genome that have been preferentially increased in frequency and fixed in a population because of their functional importance in specific processes. These regions can be detected because of their lower genetic variability and specific regional linkage disequilibrium (LD) patterns.
Methods
By comparing the differences in regional LD variation between dairy and beef cattle types, and between indicine and taurine subspecies, we aim at finding signatures of selection for production and adaptation in cattle breeds. The VarLD method was applied to compare the LD variation in the autosomal genome between breeds, including Angus and Brown Swiss, representing taurine breeds, and Nelore and Gir, representing indicine breeds. Genomic regions containing the top 0.01 and 0.1 percentile of signals were characterized using the UMD3.1 Bos taurus genome assembly to identify genes in those regions and compared with previously reported selection signatures and regions with copy number variation.
Results
For all comparisons, the top 0.01 and 0.1 percentile included 26 and 165 signals and 17 and 125 genes, respectively, including TECRL, BT.23182 or FPPS, CAST, MYOM1, UVRAG and DNAJA1.
Conclusions
The VarLD method is a powerful tool to identify differences in linkage disequilibrium between cattle populations and putative signatures of selection with potential adaptive and productive importance.
doi:10.1186/1297-9686-46-19
PMCID: PMC4014805  PMID: 24592996
5.  Accuracy of genomic predictions in Bos indicus (Nellore) cattle 
Background
Nellore cattle play an important role in beef production in tropical systems and there is great interest in determining if genomic selection can contribute to accelerate genetic improvement of production and fertility in this breed. We present the first results of the implementation of genomic prediction in a Bos indicus (Nellore) population.
Methods
Influential bulls were genotyped with the Illumina Bovine HD chip in order to assess genomic predictive ability for weight and carcass traits, gestation length, scrotal circumference and two selection indices. 685 samples and 320 238 single nucleotide polymorphisms (SNPs) were used in the analyses. A forward-prediction scheme was adopted to predict the genomic breeding values (DGV). In the training step, the estimated breeding values (EBV) of bulls were deregressed (dEBV) and used as pseudo-phenotypes to estimate marker effects using four methods: genomic BLUP with or without a residual polygenic effect (GBLUP20 and GBLUP0, respectively), a mixture model (Bayes C) and Bayesian LASSO (BLASSO). Empirical accuracies of the resulting genomic predictions were assessed based on the correlation between DGV and dEBV for the testing group.
Results
Accuracies of genomic predictions ranged from 0.17 (navel at weaning) to 0.74 (finishing precocity). Across traits, Bayesian regression models (Bayes C and BLASSO) were more accurate than GBLUP. The average empirical accuracies were 0.39 (GBLUP0), 0.40 (GBLUP20) and 0.44 (Bayes C and BLASSO). Bayes C and BLASSO tended to produce deflated predictions (i.e. slope of the regression of dEBV on DGV greater than 1). Further analyses suggested that higher-than-expected accuracies were observed for traits for which EBV means differed significantly between two breeding subgroups that were identified in a principal component analysis based on genomic relationships.
Conclusions
Bayesian regression models are of interest for future applications of genomic selection in this population, but further improvements are needed to reduce deflation of their predictions. Recurrent updates of the training population would be required to enable accurate prediction of the genetic merit of young animals. The technical feasibility of applying genomic prediction in a Bos indicus (Nellore) population was demonstrated. Further research is needed to permit cost-effective selection decisions using genomic information.
doi:10.1186/1297-9686-46-17
PMCID: PMC4014866  PMID: 24575732
6.  Genome-Wide Mapping of Loci Explaining Variance in Scrotal Circumference in Nellore Cattle 
PLoS ONE  2014;9(2):e88561.
The reproductive performance of bulls has a high impact on the beef cattle industry. Scrotal circumference (SC) is the most recorded reproductive trait in beef herds, and is used as a major selection criterion to improve precocity and fertility. The characterization of genomic regions affecting SC can contribute to the identification of diagnostic markers for reproductive performance and uncover molecular mechanisms underlying complex aspects of bovine reproductive biology. In this paper, we report a genome-wide scan for chromosome segments explaining differences in SC, using data of 861 Nellore bulls (Bos indicus) genotyped for over 777,000 single nucleotide polymorphisms. Loci that excel from the genome background were identified on chromosomes 4, 6, 7, 10, 14, 18 and 21. The majority of these regions were previously found to be associated with reproductive and body size traits in cattle. The signal on chromosome 14 replicates the pleiotropic quantitative trait locus encompassing PLAG1 that affects male fertility in cattle and stature in several species. Based on intensive literature mining, SP4, MAGEL2, SH3RF2, PDE5A and SNAI2 are proposed as novel candidate genes for SC, as they affect growth and testicular size in other animal models. These findings contribute to linking reproductive phenotypes to gene functions, and may offer new insights on the molecular biology of male fertility.
doi:10.1371/journal.pone.0088561
PMCID: PMC3928245  PMID: 24558400
7.  Evaluation of the lasso and the elastic net in genome-wide association studies 
Frontiers in Genetics  2013;4:270.
The number of publications performing genome-wide association studies (GWAS) has increased dramatically. Penalized regression approaches have been developed to overcome the challenges caused by the high dimensional data, but these methods are relatively new in the GWAS field. In this study we have compared the statistical performance of two methods (the least absolute shrinkage and selection operator—lasso and the elastic net) on two simulated data sets and one real data set from a 50 K genome-wide single nucleotide polymorphism (SNP) panel of 5570 Fleckvieh bulls. The first simulated data set displays moderate to high linkage disequilibrium between SNPs, whereas the second simulated data set from the QTLMAS 2010 workshop is biologically more complex. We used cross-validation to find the optimal value of regularization parameter λ with both minimum MSE and minimum MSE + 1SE of minimum MSE. The optimal λ values were used for variable selection. Based on the first simulated data, we found that the minMSE in general picked up too many SNPs. At minMSE + 1SE, the lasso didn't acquire any false positives, but selected too few correct SNPs. The elastic net provided the best compromise between few false positives and many correct selections when the penalty weight α was around 0.1. However, in our simulation setting, this α value didn't result in the lowest minMSE + 1SE. The number of selected SNPs from the QTLMAS 2010 data was after correction for population structure 82 and 161 for the lasso and the elastic net, respectively. In the Fleckvieh data set after population structure correction lasso and the elastic net identified from 1291 to 1966 important SNPs for milk fat content, with major peaks on chromosomes 5, 14, 15, and 20. Hence, we can conclude that it is important to analyze GWAS data with both the lasso and the elastic net and an alternative tuning criterion to minimum MSE is needed for variable selection.
doi:10.3389/fgene.2013.00270
PMCID: PMC3850240  PMID: 24363662
lasso; elastic net; simulation; GWAS; population structure; cattle
8.  Estimating autozygosity from high-throughput information: effects of SNP density and genotyping errors 
Background
Runs of homozygosity are long, uninterrupted stretches of homozygous genotypes that enable reliable estimation of levels of inbreeding (i.e., autozygosity) based on high-throughput, chip-based single nucleotide polymorphism (SNP) genotypes. While the theoretical definition of runs of homozygosity is straightforward, their empirical identification depends on the type of SNP chip used to obtain the data and on a number of factors, including the number of heterozygous calls allowed to account for genotyping errors. We analyzed how SNP chip density and genotyping errors affect estimates of autozygosity based on runs of homozygosity in three cattle populations, using genotype data from an SNP chip with 777 972 SNPs and a 50 k chip.
Results
Data from the 50 k chip led to overestimation of the number of runs of homozygosity that are shorter than 4 Mb, since the analysis could not identify heterozygous SNPs that were present on the denser chip. Conversely, data from the denser chip led to underestimation of the number of runs of homozygosity that were longer than 8 Mb, unless the presence of a small number of heterozygous SNP genotypes was allowed within a run of homozygosity.
Conclusions
We have shown that SNP chip density and genotyping errors introduce patterns of bias in the estimation of autozygosity based on runs of homozygosity. SNP chips with 50 000 to 60 000 markers are frequently available for livestock species and their information leads to a conservative prediction of autozygosity from runs of homozygosity longer than 4 Mb. Not allowing heterozygous SNP genotypes to be present in a homozygosity run, as has been advocated for human populations, is not adequate for livestock populations because they have much higher levels of autozygosity and therefore longer runs of homozygosity. When allowing a small number of heterozygous calls, current software does not differentiate between situations where these calls are adjacent and therefore indicative of an actual break of the run versus those where they are scattered across the length of the homozygous segment. Simple graphical tests that are used in this paper are a current, yet tedious solution.
doi:10.1186/1297-9686-45-42
PMCID: PMC4176748  PMID: 24168655
9.  A Novel qPCR Assay for the Detection of African Animal Trypanosomosis in Trypanotolerant and Trypanosusceptible Cattle Breeds 
This study was conducted to (i) determine the prevalence of African Animal Trypanosomosis (AAT) in tsetse challenged areas, (ii) compare conventional with qPCR detection systems and (iii) evaluate the host genetic background and biology as risk factors. AAT prevalence studies are often confronted with low levels of parasitaemia. Hence, we designed a novel qPCR assay using primers and species specific probes amplifying the Internal Transcribed Spacer 1 (ITS1) gene. Thereby all three AAT species could be detected simultaneously. 368 individuals from three cattle types (Baoulé, Zebu and hybrids) originating from 72 farms in Burkina Faso were analysed. Farmers were interviewed and morphometric measurements of the cattle taken. A chi-squared test and a logistic regression model were calculated to detect associations with infection. In our study, the overall rate of prevalence detected with the novel qPCR assay was 11.14%. Compared to conventional PCR we identified a concordance of 91.30%. We tested 41 animals positive for trypanosome DNA, five animals showed multiple infections. Zebus were twice as often infected (21.74%) compared to Baoulé (9.70%) and hybrids (9.57%). Trypanosoma vivax is the dominant species (9.24%), as compared to T. congolense (2.44%) and T. brucei (0.82%). The chi-squared tests linking the infection events to the breeds (Zebu vs. Baoulé and Zebu vs. hybrids) were on the border of significance. No significant association with other tested parameters could be detected. We introduce a novel qPCR technique for the fast, sensitive and simultaneous detection of the three AAT species. Our results suggest that associations with breed and infection exist since Zebu cattle are more likely to be infected compared to Baoulé and hybrids. Indigenous taurine cattle breeds, like the Baoulé, therefore provide a unique and valuable genetic resource.
Author Summary
African Animal Trypanosomosis (AAT) is a neglected tropical disease heavily impacting on the poor. Sensitive diagnostic tools are needed since actual parasitaemia levels can be very low, particularly in chronically infected or trypanotolerant animals. Hence, we present a novel real-time PCR (qPCR) assay for the simultaneous detection of the three AAT species (T. congolense, T. brucei and T. vivax). Thereby infected animals can be accurately detected in one step. 368 individuals from three cattle types (Baoulé, Zebu and hybrids) originating from 72 farms in Burkina Faso were analysed. Farmers were interviewed and morphometric measurements of the cattle taken to detect potential risk factors of infection. In our study, the overall rate of prevalence detected with the novel qPCR assay was 11.14% (41/368) compared to 10.87% (40/368) with conventional PCR. Zebus are most often infected (21.74%) compared to Baoulé (9.70%) and hybrid (9.57%) cattle. Except for breed, no significant correlation with other tested parameters could be detected. Baoulé show significantly less infections and therefore provide a unique and valuable genetic resource. In summary, with this novel qPCR technique the three AAT species can be simultaneously detected in a fast and sensitive manner.
doi:10.1371/journal.pntd.0002345
PMCID: PMC3744421  PMID: 23967357
10.  Optimization of selection for growth in Menz Sheep while minimizing inbreeding depression in fitness traits 
The genetic trends in fitness (inbreeding, fertility and survival) of a closed nucleus flock of Menz sheep under selection during ten years for increased body weight were investigated to evaluate the consequences of selection for body weight on fitness. A mate selection tool was used to optimize in retrospect the actual selection and matings conducted over the project period to assess if the observed genetic gains in body weight could have been achieved with a reduced level of inbreeding. In the actual selection, the genetic trends for yearling weight, fertility of ewes and survival of lambs were 0.81 kg, –0.00026% and 0.016% per generation. The average inbreeding coefficient remained zero for the first few generations and then tended to increase over generations. The genetic gains achieved with the optimized retrospective selection and matings were highly comparable with the observed values, the correlation between the average breeding values of lambs born from the actual and optimized matings over the years being 0.99. However, the level of inbreeding with the optimized mate selections remained zero until late in the years of selection. Our results suggest that an optimal selection strategy that considers both genetic merits and coancestry of mates should be adopted to sustain the Menz sheep breeding program.
doi:10.1186/1297-9686-45-20
PMCID: PMC3699396  PMID: 23783076
11.  Genome-wide association study for birth weight in Nellore cattle points to previously described orthologous genes affecting human and bovine height 
BMC Genetics  2013;14:52.
Background
Birth weight (BW) is an economically important trait in beef cattle, and is associated with growth- and stature-related traits and calving difficulty. One region of the cattle genome, located on Bos primigenius taurus chromosome 14 (BTA14), has been previously shown to be associated with stature by multiple independent studies, and contains orthologous genes affecting human height. A genome-wide association study (GWAS) for BW in Brazilian Nellore cattle (Bos primigenius indicus) was performed using estimated breeding values (EBVs) of 654 progeny-tested bulls genotyped for over 777,000 single nucleotide polymorphisms (SNPs).
Results
The most significant SNP (rs133012258, PGC = 1.34 × 10-9), located at BTA14:25376827, explained 4.62% of the variance in BW EBVs. The surrounding 1 Mb region presented high identity with human, pig and mouse autosomes 8, 4 and 4, respectively, and contains the orthologous height genes PLAG1, CHCHD7, MOS, RPS20, LYN, RDHE2 (SDR16C5) and PENK. The region also overlapped 28 quantitative trait loci (QTLs) previously reported in literature by linkage mapping studies in cattle, including QTLs for birth weight, mature height, carcass weight, stature, pre-weaning average daily gain, calving ease, and gestation length.
Conclusions
This study presents the first GWAS applying a high-density SNP panel to identify putative chromosome regions affecting birth weight in Nellore cattle. These results suggest that the QTLs on BTA14 associated with body size in taurine cattle (Bos primigenius taurus) also affect birth weight and size in zebu cattle (Bos primigenius indicus).
doi:10.1186/1471-2156-14-52
PMCID: PMC3683327  PMID: 23758625
GWAS; Birth weight; Bos primigenius indicus; Nellore cattle; Stature
12.  Detecting Loci under Recent Positive Selection in Dairy and Beef Cattle by Combining Different Genome-Wide Scan Methods 
PLoS ONE  2013;8(5):e64280.
As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different methodologies, it is strong evidence that the locus has been under past selection. In this paper, a straightforward frequentist approach based on the Stouffer Method to combine P-values across different tests for evidence of recent positive selection in common variations, as well as strategies for extracting biological information from the detected signals, were described and applied to high density single nucleotide polymorphism (SNP) data generated from dairy and beef cattle (taurine and indicine). The ancestral Bovinae allele state of over 440,000 SNP is also reported. Using this combination of methods, highly significant (P<3.17×10−7) population-specific sweeps pointing out to candidate genes and pathways that may be involved in beef and dairy production were identified. The most significant signal was found in the Cornichon homolog 3 gene (CNIH3) in Brown Swiss (P = 3.82×10−12), and may be involved in the regulation of pre-ovulatory luteinizing hormone surge. Other putative pathways under selection are the glucolysis/gluconeogenesis, transcription machinery and chemokine/cytokine activity in Angus; calpain-calpastatin system and ribosome biogenesis in Brown Swiss; and gangliosides deposition in milk fat globules in Gyr. The composite method, combined with the strategies applied to retrieve functional information, may be a useful tool for surveying genome-wide selective sweeps and providing insights in to the source of selection.
doi:10.1371/journal.pone.0064280
PMCID: PMC3655949  PMID: 23696874
13.  Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses 
PLoS Genetics  2013;9(2):e1003248.
Abstract
The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period. We estimated narrow sense heritability (h2), and we decomposed this parameter into polygenic heritability (h2POLY), heritability due to the Grey (STX17) mutation (h2STX17), and heritability due to agouti (ASIP) locus (h2ASIP). A high heritability was found for greying (h2 = 0.79), vitiligo (h2 = 0.63), and speckling (h2 = 0.66), while a moderate heritability was estimated for melanoma (h2 = 0.37). The additive component of ASIP was significantly different from zero only for melanoma (h2ASIP = 0.02). STX17 controlled large proportions of phenotypic variance (h2STX17 = 0.18–0.55) and overall heritability (h2STX17/h2 = 0.28–0.83) for all traits. Genetic correlations among traits were estimated as moderate to high, primarily due to the effects of the STX17 locus. Nevertheless, the correlation between progressive greying and vitiligo-like depigmentation remained large even after taking into account the effects of STX17. We presented a model where four traits with complex inheritance patterns are strongly influenced by a single mutation. This is in line with evidence of recent studies in domestic animals indicating that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. Furthermore, we demonstrated that the STX17 mutation explains to a large extent the moderate to high genetic correlations among traits, providing an example of strong pleiotropic effects caused by a single gene.
Author Summary
Clarifying the genetic architecture of complex traits is a problem with profound implications for agriculture, biology, and medicine. Using data from Lipizzan horses with the grey coat phenotype, we present an example of a single mutation (intronic duplication in STX17) that explains 18%–55% of phenotypic variation in four complex traits, while polygenic background additive effects also explain 11%–57% of phenotypic variation. This study provides a prime example of complex traits being influenced by genes of moderate-to-large effect and supports further the evidence of recent studies in domestic animals that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. We further show that the STX17 mutation accounts for a large proportion of the estimated genetic correlations between the traits. This case of strong pleiotropic effects of a single mutation on complex traits makes this work of significant general interest for biology and medicine.
doi:10.1371/journal.pgen.1003248
PMCID: PMC3567150  PMID: 23408897
14.  Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses 
BMC Genomics  2012;13:365.
Background
Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation.
Results
We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the ~350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present.
Conclusions
These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.
doi:10.1186/1471-2164-13-365
PMCID: PMC3443021  PMID: 22857264
STX17; Melanoma; Hair greying; Copy number variation; Melanocytes
15.  An Unusual Splice Defect in the Mitofusin 2 Gene (MFN2) Is Associated with Degenerative Axonopathy in Tyrolean Grey Cattle 
PLoS ONE  2011;6(4):e18931.
Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle.
doi:10.1371/journal.pone.0018931
PMCID: PMC3078137  PMID: 21526202
16.  Heritability of longevity in Large White and Landrace sows using continuous time and grouped data models 
Background
Using conventional measurements of lifetime, it is not possible to differentiate between productive and non-productive days during a sow's lifetime and this can lead to estimated breeding values favoring less productive animals. By rescaling the time axis from continuous to several discrete classes, grouped survival data (discrete survival time) models can be used instead.
Methods
The productive life length of 12319 Large White and 9833 Landrace sows was analyzed with continuous scale and grouped data models. Random effect of herd*year, fixed effects of interaction between parity and relative number of piglets, age at first farrowing and annual herd size change were included in the analysis. The genetic component was estimated from sire, sire-maternal grandsire, sire-dam, sire-maternal grandsire and animal models, and the heritabilities computed for each model type in both breeds.
Results
If age at first farrowing was under 43 weeks or above 60 weeks, the risk of culling sows increased. An interaction between parity and relative litter size was observed, expressed by limited culling during first parity and severe risk increase of culling sows having small litters later in life. In the Landrace breed, heritabilities ranged between 0.05 and 0.08 (s.e. 0.014-0.020) for the continuous and between 0.07 and 0.11 (s.e. 0.016-0.023) for the grouped data models, and in the Large White breed, they ranged between 0.08 and 0.14 (s.e. 0.012-0.026) for the continuous and between 0.08 and 0.13 (s.e. 0.012-0.025) for the grouped data models.
Conclusions
Heritabilities for length of productive life were similar with continuous time and grouped data models in both breeds. Based on these results and because grouped data models better reflect the economical needs in meat animals, we conclude that grouped data models are more appropriate in pig.
doi:10.1186/1297-9686-42-13
PMCID: PMC2879236  PMID: 20465803
17.  Assignment of chromosomal locations for unassigned SNPs/scaffolds based on pair-wise linkage disequilibrium estimates 
BMC Bioinformatics  2010;11:171.
Background
Recent developments of high-density SNP chips across a number of species require accurate genetic maps. Despite rapid advances in genome sequence assembly and availability of a number of tools for creating genetic maps, the exact genome location for a number of SNPs from these SNP chips still remains unknown. We have developed a locus ordering procedure based on linkage disequilibrium (LODE) which provides estimation of the chromosomal positions of unaligned SNPs and scaffolds. It also provides an alternative means for verification of genetic maps. We exemplified LODE in cattle.
Results
The utility of the LODE procedure was demonstrated using data from 1,943 bulls genotyped for 73,569 SNPs across three different SNP chips. First, the utility of the procedure was tested by analysing the masked positions of 1,500 randomly-chosen SNPs with known locations (50 from each chromosome), representing three classes of minor allele frequencies (MAF), namely >0.05, 0.01
Conclusion
The LODE procedure described in this study is an efficient and accurate method for positioning SNPs (MAF>0.05), for validating and checking the quality of a genome assembly, and offers a means for positioning of unordered scaffolds containing SNPs. The LODE procedure will be helpful in refining genome sequence assemblies, especially those being created from next-generation sequencing where high-throughput SNP discovery and genotyping platforms are integrated components of genome analysis.
doi:10.1186/1471-2105-11-171
PMCID: PMC2859757  PMID: 20370931
The study investigated the population structure, diversity and differentiation of almost all of the ecotypes representing the African Ankole Longhorn cattle breed on the basis of morphometric (shape and size), genotypic and spatial distance data. Twentyone morphometric measurements were used to describe the morphology of 439 individuals from 11 sub-populations located in five countries around the Great Lakes region of central and eastern Africa. Additionally, 472 individuals were genotyped using 15 DNA microsatellites. Femoral length, horn length, horn circumference, rump height, body length and fore-limb circumference showed the largest differences between regions. An overall FST index indicated that 2.7% of the total genetic variation was present among sub-populations. The least differentiation was observed between the two sub-populations of Mbarara south and Luwero in Uganda, while the highest level of differentiation was observed between the Mugamba in Burundi and Malagarasi in Tanzania. An estimated membership of four for the inferred clusters from a model-based Bayesian approach was obtained. Both analyses on distance-based and model-based methods consistently isolated the Mugamba sub-population in Burundi from the others.
doi:10.1186/1297-9686-40-5-467
PMCID: PMC2674885  PMID: 18694545
Ankole Longhorn cattle; microsatellite; geometric morphometric; genetic distance; spatial distance
Genetics, Selection, Evolution : GSE  2003;35(Suppl 1):S177-S190.
To investigate whether the equine major histocompatibility complex (MHC) gene region influences the production of mould-specific immunoglobulin E antibodies (IgE), alleles of the equine leukocyte antigen (ELA-A) locus and three microsatellite markers (UM-011, HTG-05 and HMS-42) located on the same chromosome as the equine MHC were determined in 448 Lipizzan horses. Statistical analyses based on composite models, showed significant associations of the ELA-A and UM-011 loci with IgE titres against the recombinant Aspergillus fumigatus 7 antigen (rAsp f 7). UM-011 was also significantly associated with IgE titres against the recombinant Aspergillus fumigatus 8 antigen (rAsp f 8). In addition to the loci mentioned above, the MHC class II DQA and DRA loci were determined in 76 Lipizzans from one stud. For IgE levels against rAsp f 7, the composite model showed the strongest association for DQA (P < 0.01) while for rAsp f 8 specific IgE levels, similarly to the results found with all 448 horses, the strongest association was found with UM-011 (P = 0.01), which is closely linked with the MHC class II DRB locus. These results suggest that the equine MHC gene region and possibly MHC class II loci, influence the specific IgE response in the horse. However, although the strongest associations were found with DQA and UM-011, this study did not distinguish if the observed effects were due to the MHC itself or to other tightly linked genes.
doi:10.1186/1297-9686-35-S1-S177
PMCID: PMC3231759  PMID: 12927090
horse; major histocompatibility complex; immunoglobulin E; specific mould allergen
Sequencing of the mtDNA control region (385 or 695 bp) of 212 Lipizzans from eight studs revealed 37 haplotypes. Distribution of haplotypes among studs was biased, including many private haplotypes but only one haplotype was present in all the studs. According to historical data, numerous Lipizzan maternal lines originating from founder mares of different breeds have been established during the breed's history, so the broad genetic base of the Lipizzan maternal lines was expected. A comparison of Lipizzan sequences with 136 sequences of domestic- and wild-horses from GenBank showed a clustering of Lipizzan haplotypes in the majority of haplotype subgroups present in other domestic horses. We assume that haplotypes identical to haplotypes of early domesticated horses can be found in several Lipizzan maternal lines as well as in other breeds. Therefore, domestic horses could arise either from a single large population or from several populations provided there were strong migrations during the early phase after domestication. A comparison of Lipizzan haplotypes with 56 maternal lines (according to the pedigrees) showed a disagreement of biological parentage with pedigree data for at least 11% of the Lipizzans. A distribution of haplotype-frequencies was unequal (0.2%–26%), mainly due to pedigree errors and haplotype sharing among founder mares.
doi:10.1186/1297-9686-34-5-635
PMCID: PMC2705438  PMID: 12427390
Lipizzan horse;  control region;  origin;  phylogeny;  pedigree

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