Obesity is associated with altered gene expression in human tastebuds.

BACKGROUND: The role of taste perception in the development and persistence of obesity is currently unclear due to conflicting results from psychophysical and other studies. No study to date has assessed whether there is an underlying fundamental difference in the physiology of taste tissue between lean and obese individuals. METHOD/SUBJECTS: We analysed the transcriptomic profile (RNA-seq) of human fungiform taste papillae biopsied from lean (n = 23) and obese (n = 13) Caucasian females (age range 18-55) to identify differences in gene expression. RESULTS: Obesity status was the major contributor to variance in global gene expression between individuals. A total of 62 genes had significantly different gene expression levels between lean and obese (P < 0.0002), with the specific taste associated genes phospholipase C beta 2 (PLCß2) and sonic hedge-hog (SHH) having significantly reduced expression in obese group. Genes associated with inflammation and immune response were the top enriched biological pathways differing between the lean and the obese groups. Analysis of a broader gene set having a twofold change in expression (2619 genes) identified three enriched theme groups (sensory perception, cell and synaptic signalling, and immune response). Further, analysis of taste associated genes identified a consistent reduction in the expression of taste-related genes (in particular reduced type II taste cell genes) in the obese compared to the lean group. CONCLUSION: The findings show obesity is associated with altered gene expression in tastebuds. Furthermore, the results suggest the tastebud microenvironment is distinctly different between lean and obese persons and, that changes in sensory gene expression contribute to this altered microenvironment. This research provides new evidence of a link between obesity and altered taste and in the future may help design strategies to combat obesity.

Mammalian genomic regulatory regions predicted by utilizing human genomics, transcriptomics, and epigenetics data.

Genome sequences for hundreds of mammalian species are available, but an understanding of their genomic regulatory regions, which control gene expression, is only beginning. A comprehensive prediction of potential active regulatory regions is necessary to functionally study the roles of the majority of genomic variants in evolution, domestication, and animal production. We developed a computational method to predict regulatory DNA sequences (promoters, enhancers, and transcription factor binding sites) in production animals (cows and pigs) and extended its broad applicability to other mammals. The method utilizes human regulatory features identified from thousands of tissues, cell lines, and experimental assays to find homologous regions that are conserved in sequences and genome organization and are enriched for regulatory elements in the genome sequences of other mammalian species. Importantly, we developed a filtering strategy, including a machine learning classification method, to utilize a very small number of species-specific experimental datasets available to select for the likely active regulatory regions. The method finds the optimal combination of sensitivity and accuracy to unbiasedly predict regulatory regions in mammalian species. Furthermore, we demonstrated the utility of the predicted regulatory datasets in cattle for prioritizing variants associated with multiple production and climate change adaptation traits and identifying potential genome editing targets.

Convergent Evolution of Slick Coat in Cattle through Truncation Mutations in the Prolactin Receptor.

Evolutionary adaptations are occasionally convergent solutions to the same problem. A mutation contributing to a heat tolerance adaptation in Senepol cattle, a New World breed of mostly European descent, results in the distinct phenotype known as slick, where an animal has shorter hair and lower follicle density across its coat than wild type animals. The causal variant, located in the 11th exon of prolactin receptor, produces a frameshift that results in a truncated protein. However, this mutation does not explain all cases of slick coats found in criollo breeds. Here, we obtained genome sequences from slick cattle of a geographically distinct criollo breed, namely Limonero, whose ancestors were originally brought to the Americas by the Spanish. These data were used to identify new causal alleles in the 11th exon of the prolactin receptor, two of which also encode shortened proteins that remove a highly conserved tyrosine residue. These new mutations explained almost 90% of investigated cases of animals that had slick coats, but which also did not carry the Senepol slick allele. These results demonstrate convergent evolution at the molecular level in a trait important to the adaptation of an animal to its environment.

Genomic correlation: harnessing the benefit of combining two unrelated populations for genomic selection.

BACKGROUND: The success of genomic selection in animal breeding hinges on the availability of a large reference population on which genomic-based predictions of additive genetic or breeding values are built. Here, we explore the benefit of combining two unrelated populations into a single reference population. METHODS: The datasets consisted of 1829 Brahman and 1973 Tropical Composite cattle with measurements on five phenotypes relevant to tropical adaptation and genotypes for 71,726 genome-wide single nucleotide polymorphisms (SNPs). The underlying genomic correlation for the same phenotype across the two breeds was explored on the basis of consistent linkage disequilibrium (LD) phase and marker effects in both breeds. RESULTS: The proportion of genetic variance explained by the entire set of SNPs ranged from 37.5 to 57.6 %. Estimated genomic correlations were drastically affected by the process used to select SNPs and went from near 0 to more than 0.80 for most traits when using the set of SNPs with significant effects and the same LD phase in the two breeds. We found that, by carefully selecting the subset of SNPs, the missing heritability can be largely recovered and accuracies in genomic predictions can be improved six-fold. However, the increases in accuracy might come at the expense of large biases. CONCLUSIONS: Our results offer hope for the effective implementation of genomic selection schemes in situations where the number of breeds is large, the sample size within any single breed is small and the breeding objective includes many phenotypes.

Non-additive genetic variation in growth, carcass and fertility traits of beef cattle.

BACKGROUND: A better understanding of non-additive variance could lead to increased knowledge on the genetic control and physiology of quantitative traits, and to improved prediction of the genetic value and phenotype of individuals. Genome-wide panels of single nucleotide polymorphisms (SNPs) have been mainly used to map additive effects for quantitative traits, but they can also be used to investigate non-additive effects. We estimated dominance and epistatic effects of SNPs on various traits in beef cattle and the variance explained by dominance, and quantified the increase in accuracy of phenotype prediction by including dominance deviations in its estimation. METHODS: Genotype data (729 068 real or imputed SNPs) and phenotypes on up to 16 traits of 10 191 individuals from Bos taurus, Bos indicus and composite breeds were used. A genome-wide association study was performed by fitting the additive and dominance effects of single SNPs. The dominance variance was estimated by fitting a dominance relationship matrix constructed from the 729 068 SNPs. The accuracy of predicted phenotypic values was evaluated by best linear unbiased prediction using the additive and dominance relationship matrices. Epistatic interactions (additive × additive) were tested between each of the 28 SNPs that are known to have additive effects on multiple traits, and each of the other remaining 729 067 SNPs. RESULTS: The number of significant dominance effects was greater than expected by chance and most of them were in the direction that is presumed to increase fitness and in the opposite direction to inbreeding depression. Estimates of dominance variance explained by SNPs varied widely between traits, but had large standard errors. The median dominance variance across the 16 traits was equal to 5% of the phenotypic variance. Including a dominance deviation in the prediction did not significantly increase its accuracy for any of the phenotypes. The number of additive × additive epistatic effects that were statistically significant was greater than expected by chance. CONCLUSIONS: Significant dominance and epistatic effects occur for growth, carcass and fertility traits in beef cattle but they are difficult to estimate precisely and including them in phenotype prediction does not increase its accuracy.

SNP discovery in nonmodel organisms: strand bias and base-substitution errors reduce conversion rates.

Single nucleotide polymorphisms (SNPs) have become the marker of choice for genetic studies in organisms of conservation, commercial or biological interest. Most SNP discovery projects in nonmodel organisms apply a strategy for identifying putative SNPs based on filtering rules that account for random sequencing errors. Here, we analyse data used to develop 4723 novel SNPs for the commercially important deep-sea fish, orange roughy (Hoplostethus atlanticus), to assess the impact of not accounting for systematic sequencing errors when filtering identified polymorphisms when discovering SNPs. We used SAMtools to identify polymorphisms in a velvet assembly of genomic DNA sequence data from seven individuals. The resulting set of polymorphisms were filtered to minimize 'bycatch'-polymorphisms caused by sequencing or assembly error. An Illumina Infinium SNP chip was used to genotype a final set of 7714 polymorphisms across 1734 individuals. Five predictors were examined for their effect on the probability of obtaining an assayable SNP: depth of coverage, number of reads that support a variant, polymorphism type (e.g. A/C), strand-bias and Illumina SNP probe design score. Our results indicate that filtering out systematic sequencing errors could substantially improve the efficiency of SNP discovery. We show that BLASTX can be used as an efficient tool to identify single-copy genomic regions in the absence of a reference genome. The results have implications for research aiming to identify assayable SNPs and build SNP genotyping assays for nonmodel organisms.

The genetic architecture of climatic adaptation of tropical cattle.

Adaptation of global food systems to climate change is essential to feed the world. Tropical cattle production, a mainstay of profitability for farmers in the developing world, is dominated by heat, lack of water, poor quality feedstuffs, parasites, and tropical diseases. In these systems European cattle suffer significant stock loss, and the cross breeding of taurine x indicine cattle is unpredictable due to the dilution of adaptation to heat and tropical diseases. We explored the genetic architecture of ten traits of tropical cattle production using genome wide association studies of 4,662 animals varying from 0% to 100% indicine. We show that nine of the ten have genetic architectures that include genes of major effect, and in one case, a single location that accounted for more than 71% of the genetic variation. One genetic region in particular had effects on parasite resistance, yearling weight, body condition score, coat colour and penile sheath score. This region, extending 20 Mb on BTA5, appeared to be under genetic selection possibly through maintenance of haplotypes by breeders. We found that the amount of genetic variation and the genetic correlations between traits did not depend upon the degree of indicine content in the animals. Climate change is expected to expand some conditions of the tropics to more temperate environments, which may impact negatively on global livestock health and production. Our results point to several important genes that have large effects on adaptation that could be introduced into more temperate cattle without detrimental effects on productivity.

A multi-trait, meta-analysis for detecting pleiotropic polymorphisms for stature, fatness and reproduction in beef cattle.

Polymorphisms that affect complex traits or quantitative trait loci (QTL) often affect multiple traits. We describe two novel methods (1) for finding single nucleotide polymorphisms (SNPs) significantly associated with one or more traits using a multi-trait, meta-analysis, and (2) for distinguishing between a single pleiotropic QTL and multiple linked QTL. The meta-analysis uses the effect of each SNP on each of n traits, estimated in single trait genome wide association studies (GWAS). These effects are expressed as a vector of signed t-values (t) and the error covariance matrix of these t values is approximated by the correlation matrix of t-values among the traits calculated across the SNP (V). Consequently, t'V-1t is approximately distributed as a chi-squared with n degrees of freedom. An attractive feature of the meta-analysis is that it uses estimated effects of SNPs from single trait GWAS, so it can be applied to published data where individual records are not available. We demonstrate that the multi-trait method can be used to increase the power (numbers of SNPs validated in an independent population) of GWAS in a beef cattle data set including 10,191 animals genotyped for 729,068 SNPs with 32 traits recorded, including growth and reproduction traits. We can distinguish between a single pleiotropic QTL and multiple linked QTL because multiple SNPs tagging the same QTL show the same pattern of effects across traits. We confirm this finding by demonstrating that when one SNP is included in the statistical model the other SNPs have a non-significant effect. In the beef cattle data set, cluster analysis yielded four groups of QTL with similar patterns of effects across traits within a group. A linear index was used to validate SNPs having effects on multiple traits and to identify additional SNPs belonging to these four groups.

Evidence for positive selection of taurine genes within a QTL region on chromosome X associated with testicular size in Australian Brahman cattle.

BACKGROUND: Previous genome-wide association studies have identified significant regions of the X chromosome associated with reproductive traits in two Bos indicus-influenced breeds: Brahman cattle and Tropical Composites. Two QTL regions on this chromosome were identified in both breeds as strongly associated with scrotal circumference measurements, a reproductive trait previously shown to be useful for selection of young bulls. Scrotal circumference is genetically correlated with early age at puberty in both male and female offspring. These QTL were located at positions 69-77 and 81-92 Mb respectively, large areas each to which a significant number of potential candidate genes were mapped. RESULTS: To further characterise these regions, a bioinformatic approach was undertaken to identify novel non-synonymous SNP within the QTL regions of interest in Brahman cattle. After SNP discovery, we used conventional molecular assay technologies to perform studies of two candidate genes in both breeds. Non-synonymous SNP mapped to Testis-expressed gene 11 (Tex11) were associated (P < 0.001) with scrotal circumference in both breeds, and associations with percentage of normal sperm cells were also observed (P < 0.05). Evidence for recent selection was found as Tex11 SNP form a haplotype segment of Bos taurus origin that is retained within Brahman and Tropical Composite cattle with greatest reproductive potential. CONCLUSIONS: Association of non-synonymous SNP presented here are a first step to functional genetic studies. Bovine species may serve as a model for studying the role of Tex11 in male fertility, warranting further in-depth molecular characterisation.

Detection of quantitative trait loci in Bos indicus and Bos taurus cattle using genome-wide association studies.

BACKGROUND: The apparent effect of a single nucleotide polymorphism (SNP) on phenotype depends on the linkage disequilibrium (LD) between the SNP and a quantitative trait locus (QTL). However, the phase of LD between a SNP and a QTL may differ between Bos indicus and Bos taurus because they diverged at least one hundred thousand years ago. Here, we test the hypothesis that the apparent effect of a SNP on a quantitative trait depends on whether the SNP allele is inherited from a Bos taurus or Bos indicus ancestor. METHODS: Phenotype data on one or more traits and SNP genotype data for 10 181 cattle from Bos taurus, Bos indicus and composite breeds were used. All animals had genotypes for 729 068 SNPs (real or imputed). Chromosome segments were classified as originating from B. indicus or B. taurus on the basis of the haplotype of SNP alleles they contained. Consequently, SNP alleles were classified according to their sub-species origin. Three models were used for the association study: (1) conventional GWAS (genome-wide association study), fitting a single SNP effect regardless of subspecies origin, (2) interaction GWAS, fitting an interaction between SNP and subspecies-origin, and (3) best variable GWAS, fitting the most significant combination of SNP and sub-species origin. RESULTS: Fitting an interaction between SNP and subspecies origin resulted in more significant SNPs (i.e. more power) than a conventional GWAS. Thus, the effect of a SNP depends on the subspecies that the allele originates from. Also, most QTL segregated in only one subspecies, suggesting that many mutations that affect the traits studied occurred after divergence of the subspecies or the mutation became fixed or was lost in one of the subspecies. CONCLUSIONS: The results imply that GWAS and genomic selection could gain power by distinguishing SNP alleles based on their subspecies origin, and that only few QTL segregate in both B. indicus and B. taurus cattle. Thus, the QTL that segregate in current populations likely resulted from mutations that occurred in one of the subspecies and can have both positive and negative effects on the traits. There was no evidence that selection has increased the frequency of alleles that increase body weight.

Fine-mapping the POLL locus in Brahman cattle yields the diagnostic marker CSAFG29.

The POLL locus has been mapped to the centromeric region of bovine chromosome 1 (BTA1) in both taurine breeds and taurine-indicine crosses in an interval of approximately 1 Mb. It has not yet been mapped in pure-bred zebu cattle. Despite several efforts, neither causative mutations in candidate genes nor a singular diagnostic DNA marker has been identified. In this study, we genotyped a total of 68 Brahman cattle and 20 Hereford cattle informative for the POLL locus for 33 DNA microsatellites, 16 of which we identified de novo from the bovine genome sequence, mapping the POLL locus to the region of the genes IFNAR2 and SYNJ1. The 303-bp allele of the new microsatellite, CSAFG29, showed strong association with the POLL allele. We then genotyped 855 Brahman cattle for CSAFG29 and confirmed the association between the 303-bp allele and POLL. To determine whether the same association was found in taurine breeds, we genotyped 334 animals of the Angus, Hereford and Limousin breeds and 376 animals of the Brangus, Droughtmaster and Santa Gertrudis composite taurine-zebu breeds. The association between the 303-bp allele and POLL was confirmed in these breeds; however, an additional allele (305 bp) was also associated but not fully predictive of POLL. Across the data, CSAFG29 was in sufficient linkage disequilibrium to the POLL allele in Australian Brahman cattle that it could potentially be used as a diagnostic marker in that breed, but this may not be the case in other breeds. Further, we provide confirmatory evidence that the scur phenotype generally occurs in animals that are heterozygous for the POLL allele.

Estimating the effect of SNP genotype on quantitative traits from pooled DNA samples.

BACKGROUND: Studies to detect associations between DNA markers and traits of interest in humans and livestock benefit from increasing the number of individuals genotyped. Performing association studies on pooled DNA samples can provide greater power for a given cost. For quantitative traits, the effect of an SNP is measured in the units of the trait and here we propose and demonstrate a method to estimate SNP effects on quantitative traits from pooled DNA data. METHODS: To obtain estimates of SNP effects from pooled DNA samples, we used logistic regression of estimated allele frequencies in pools on phenotype. The method was tested on a simulated dataset, and a beef cattle dataset using a model that included principal components from a genomic correlation matrix derived from the allele frequencies estimated from the pooled samples. The performance of the obtained estimates was evaluated by comparison with estimates obtained using regression of phenotype on genotype from individual samples of DNA. RESULTS: For the simulated data, the estimates of SNP effects from pooled DNA are similar but asymptotically different to those from individual DNA data. Error in estimating allele frequencies had a large effect on the accuracy of estimated SNP effects. For the beef cattle dataset, the principal components of the genomic correlation matrix from pooled DNA were consistent with known breed groups, and could be used to account for population stratification. Correctly modeling the contemporary group structure was essential to achieve estimates similar to those from individual DNA data, and pooling DNA from individuals within groups was superior to pooling DNA across groups. For a fixed number of assays, pooled DNA samples produced results that were more correlated with results from individual genotyping data than were results from one random individual assayed from each pool. CONCLUSIONS: Use of logistic regression of allele frequency on phenotype makes it possible to estimate SNP effects on quantitative traits from pooled DNA samples. With pooled DNA samples, genotyping costs are reduced, and in cases where trait records are abundant this approach is promising to obtain SNP associations for marker-assisted selection.

Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection.

Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.

The RIPK2 gene: a positional candidate for tick burden supported by genetic associations in cattle and immunological response of knockout mouse.

Ticks and tick-borne diseases have a detrimental impact on livestock production causing estimated losses of around $200 million per year in Australia alone. Host resistance to ticks is heritable, within-breed heritability estimates being around 0.35, and with large differences between breeds. Previously a QTL for tick burden was detected on BTA14 at ~72 Mb distal to the centromere, near the gene receptor-interacting serine-threonine kinase 2 (RIPK2). To identify polymorphisms in this region, we sequenced all exons of the RIPK2 gene, identifying 46 single nucleotide polymorphism (SNP). Using SNP from RIPK2 as well as SNP from the bovine genome sequence, we genotyped two samples, one of 1,122 taurine dairy cattle and one of 761 zebu and zebu composite beef cattle. We confirmed that SNP and haplotypes from this region, including from RIPK2, were associated with tick burden in both dairy and beef cattle. To determine whether RIPK2 influences response to tick salivary gland extract (SGE), an immunisation experiment with tick SGE in a RIPK2 knockout (RIPK2 −/−) mouse strain was conducted. There was a significant (P < 0.05) reduction in IgG production in the RIPK2 −/− mouse in response to the SGE compared to its background strain C57BL/ 6 as well as the outbred CD1 mouse strain. In addition, antibodies generated by RIPK2 −/− mice recognised a different set of antigens within SGE when compared to parental-derived antibodies. In summary, the SNP association with tick burden at BTA14 was confirmed and quantitative and qualitative differences in antibody production were observed between RIPK2 −/− and wild-type mice.

Molecular genetic approaches for identifying the basis of variation in resistance to tick infestation in cattle.

In recent years there has been renewed interest in the adaptation of cattle to challenging environments, largely driven by advances in genomic methods. The current interest in tick resistance is understandable given the major production and welfare implications of tick infestation in tropical and subtropical zones where around 70% of beef cattle are located. Heritability for tick burden in cattle has been shown to range about 0.30, which is sufficient to result in the success of some programs of selection for tick resistance in cattle. Gene-expression studies strongly indicate that both immune and non-immune mechanisms are associated with tick resistance in cattle. Recent quantitative-trait mapping studies have identified chromosome segments and single nucleotide polymorphisms associated with tick burden, but no causal variant has been identified so far. Most of the genetic markers identified for tick burden explain a relatively small proportion of the variance, which is typical of markers for quantitative traits. This leads to the conclusion that panels of multiple markers for tick resistance rather than a single marker will most likely be developed, possibly involving specific panels for zebu or taurine breeds, which could be used for future selection and breeding programs in cattle.

The effect of measurement error of phenotypes on genome wide association studies.

BACKGROUND: There is an unspoken assumption that imprecision of measurement of phenotypes will not have large systematic effects on the location of significant associations in a genome wide association study (GWAS). In this report, the effects of two independent measurements of the same trait, subcutaneous fat thickness, were examined in GWAS of 940 individuals. RESULTS: The trait values obtained by two independent groups working to the same trait definition were correlated with r = 0.72. The allele effects obtained from the two analyses were only moderately correlated, with r = 0.53, and there was one significant (P < 0.0001) association in common to the two measurements. The correlation between allele effects was approximately equal to the square of the correlation between the trait measurements. An important quantitative trait locus (QTL) on BTA14 appeared to be shifted distally by 1 Mb along the chromosome. The divergence in GWAS was stronger with data coded into two discrete classes. Univariate trimming of the top and bottom 5% of data, a method used to control for erroneous trait values, decreased the similarity between the GWAS and increased the apparent shift of the QTL on BTA14. Stringent bivariate trimming of data, using only trait values that were similar to each other in the two data sets, substantially improved the correlation of trait values and allele effects in the GWAS, and showed evidence for two QTL on BTA14 separated by 1 Mb. Despite the reduction in sample size due to trimming, more SNP were significant. Using the mean of the two measurements of the trait was not as efficient as bivariate trimming. CONCLUSIONS: It is recommended that trait values in GWAS experiments be examined for repeatability before the experiment is performed. For traits that do not have high repeatability (r < 0.95), two or more independent measurements of the same trait should be obtained for all samples, and individuals genotyped that have highly correlated trait measurements.

Analysis of copy number variants in the cattle genome.

Copy number variation (CNV) is likely to be an important component of heritable variation in livestock. To characterise CNVs in cattle, we performed a genome wide survey to determine the number, location and gene content of these genomic features. A tiling oligonucleotide array with ~385,000 probes was used for comparative genomic hybridisation of both taurine and zebu cattle. Using a conservative set of calling criteria, a total of 51 CNV were detected that collectively spanned approximately half of one percent of the bovine genome. The size of the average CNV within each animal ranged from 213 kb up to 335 kb. Half of the CNV were detected in a single animal only, whilst the remainder was independently identified in multiple individuals. Analysis was performed to determine the gene content for each CNV region. This revealed that the majority of CNV (82%) spanned at least one gene, with a number of CNV containing genes which are known to control aspects of phenotypic variation in cattle. Whilst additional studies are required to determine the impact of individual CNV, this study confirmed them as an important class of genomic variation in cattle.

Haplotype analysis improved evidence for candidate genes for intramuscular fat percentage from a genome wide association study of cattle.

In genome wide association studies (GWAS), haplotype analyses of SNP data are neglected in favour of single point analysis of associations. In a recent GWAS, we found that none of the known candidate genes for intramuscular fat (IMF) had been identified. In this study, data from the GWAS for these candidate genes were re-analysed as haplotypes. First, we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain-calpastatin complex and musculus longissimus lumborum peak force (LLPF), because these genes had been confirmed through single point analysis in the GWAS. Then, for intramuscular fat percent (IMF), we found significant partial haplotype substitution effects for the genes ADIPOQ and CXCR4, as well as suggestive associations to the genes CEBPA, FASN, and CAPN1. Haplotypes for these genes explained 80% more of the phenotypic variance compared to the best single SNP. For some genes the analyses suggested that there was more than one causative mutation in some genes, or confirmed that some causative mutations are limited to particular subgroups of a species. Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses. Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data, would be a useful method to extract more information from these data sets, and may contribute to reducing the missing heritability problem.

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes.

BACKGROUND: About forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation. RESULTS: The current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified. CONCLUSIONS: Transcriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.

Haplotypes that include the integrin alpha 11 gene are associated with tick burden in cattle.

BACKGROUND: Infestations on cattle by the ectoparasite Boophilus (Rhipicephalus) microplus (cattle tick) impact negatively on animal production systems. Host resistance to tick infestation has a low to moderate heritability in the range 0.13 - 0.64 in Australia. Previous studies identified a QTL on bovine chromosome 10 (BTA10) linked to tick burden in cattle. RESULTS: To confirm these associations, we collected genotypes of 17 SNP from BTA10, including three obtained by sequencing part of the ITGA11 (Integrin alpha 11) gene. Initially, we genotyped 1,055 dairy cattle for the 17 SNP, and then genotyped 557 Brahman and 216 Tropical Composite beef cattle for 11 of the 17 SNP. In total, 7 of the SNP were significantly (P < 0.05) associated with tick burden tested in any of the samples. One SNP, ss161109814, was significantly (P < 0.05) associated with tick burden in both the taurine and the Brahman sample, but the favourable allele was different. Haplotypes for three and for 10 SNP were more significantly (P < 0.001) associated with tick burden than SNP analysed individually. Some of the common haplotypes with the largest sample sizes explained between 1.3% and 1.5% of the residual variance in tick burden. CONCLUSIONS: These analyses confirm the location of a QTL affecting tick burden on BTA10 and position it close to the ITGA11 gene. The presence of a significant association in such widely divergent animals suggests that further SNP discovery in this region to detect causal mutations would be warranted.