Bovine polledness--an autosomal dominant trait with allelic heterogeneity

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ～381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations.     

SNP-based association mapping of the polled gene in divergent cattle breeds

Naturally, hornless cattle are called polled. Although the POLL locus could be assigned to a c. 1.36‐Mb interval in the centromeric region of BTA1, the underlying genetic basis for the polled trait is still unknown. Here, an association mapping design was set up to refine the candidate region of the polled trait for subsequent high‐throughput sequencing. The case group comprised 101 homozygous polled animals from nine divergent cattle breeds, the majority represented by Galloway, Angus, Fleckvieh and Holstein Friesian. Additionally, this group included some polled individuals of Blonde d’Aquitaine, Charolais, Hereford, Jersey and Limousin breeds. The control group comprised horned Belgian Blue, Fleckvieh, Holstein Friesian and Illyrian Bu?a cattle. A genome‐wide scan using 49 163 SNPs was performed, which revealed one shared homozygous haplotype block consisting of nine neighbouring SNPs in all polled animals. This segment defines a 381‐kb interval on BTA1 that we consider to be the most likely location of the POLL mutation. Our results further demonstrate that the polled‐associated haplotype is also frequent in horned animals included in this study, and thus the haplotype as such cannot be used for population‐wide genetic testing. The actual trait‐associated haplotype may be revealed by using higher‐density SNP arrays. For the final identification of the causal mutation, we suggest high‐throughput sequencing of the entire candidate region, because the identification of functional candidate genes is difficult owing to the lack of a comparable model.     

Polledness in Argentinean Creole cattle,five centuries surviving

Polledness has been shown to have autosomal Mendelian inheritance, with the polled locus being dominant to the horned locus. This trait was mapped to the BTA1 centromeric end in several breeds. One of the distinctive attributes of Creole cattle, such as the Argentinean Creole, is the presence of long, lyre‐shaped horns. However, polled native animals were reported before the introduction of modern selected European breeds. Here, we studied the origin of the polled mutation, either independent or introgressed, in a Creole line from the Creole cattle founder group at the IIACS‐INTA Leales Experimental Station (northwest Argentina). The study sample (65 animals: 26 horned and 39 polled) was genotyped using high‐density SNP microarrays and three previously reported genetic markers (P_202ID, P_80kbID and P_G). A genome‐wide association study, selection signatures, linkage disequilibrium analysis and copy number variations were used to detect the responsible region and the segregating haplotypes/alleles. The interval mapped in the Leales herd (1.23–2.13 Mb) overlapped with the region previously reported in several European cattle breeds, suggesting that the same locus could be segregating in this population. The previously reported variants P_F and P_G were not detected, thus dismissing the Holstein‐Friesian and Nellore origins of the polled phenotype in this native breed. Conversely, the presence of the Celtic variant P_C suggests an almost complete co‐segregation. The cluster analysis rejected the hypothesis of recent introgression, which is compatible with the historical record of polled Creole cattle in northwest Argentina.     

Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle

Background

Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes.

Results

A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P = 1.79 × 10⁻⁵) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2.

Conclusions

Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1483-7) contains supplementary material, which is available to authorized users.     

Analytical and statistical consideration on the use of the ISAG-ICAR-SNP bovine panel for parentage control,using the Illumina BeadChip technology: example on the German Holstein population

Background

Parentage control is moving from short tandem repeats- to single nucleotide polymorphism (SNP) systems. For SNP-based parentage control in cattle, the ISAG-ICAR Committee proposes a set of 100/200 SNPs but quality criteria are lacking. Regarding German Holstein-Friesian cattle with only a limited number of evaluated individuals, the exclusion probability is not well-defined. We propose a statistical procedure for excluding single SNPs from parentage control, based on case-by-case evaluation of the GenCall score, to minimize parentage exclusion, based on miscalled genotypes. Exclusion power of the ISAG-ICAR SNPs used for the German Holstein-Friesian population was adjusted based on the results of more than 25 000 individuals.

Results

Experimental data were derived from routine genomic selection analyses of the German Holstein-Friesian population using the Illumina BovineSNP50 v2 BeadChip (20 000 individuals) or the EuroG10K variant (7000 individuals). Averages and standard deviations of GenCall scores for the 200 SNPs of the ISAG-ICAR recommended panel were calculated and used to calculate the downward Z-value. Based on minor allelic frequencies in the Holstein-Friesian population, one minus exclusion probability was equal to 1.4×10⁻¹⁰ and 7.2×10⁻²⁶, with one and two parents, respectively. Two monomorphic SNPs from the 100-SNP ISAG-ICAR core-panel did not contribute. Simulation of 10 000 parentage control combinations, using the GenCall score data from both BeadChips, showed that with a Z-value greater than 3.66 only about 2.5% parentages were excluded, based on the ISAG-ICAR recommendations (core-panel: ≥ 90 SNPs for one, ≥ 85 SNPs for two parents). When applied to real data from 1750 single parentage assessments, the optimal threshold was determined to be Z = 5.0, with only 34 censored cases and reduction to four (0.2%) doubtful parentages. About 70 parentage exclusions due to weak genotype calls were avoided, whereas true exclusions (n = 34) were unaffected.

Conclusions

Using SNPs for parentage evaluation provides a high exclusion power also for parent identification. SNPs with a low GenCall score show a high tendency towards intra-molecular secondary structures and substantially contribute to false exclusion of parentages. We propose a method that controls this error without excluding too many parent combinations from the evaluation.

Electronic supplementary material

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Genome-wide association study for calving performance using high-density genotypes in dairy and beef cattle

Background

Calving difficulty and perinatal mortality are prevalent in modern-day cattle production systems. It is well-established that there is a genetic component to both traits, yet little is known about their underlying genomic architecture, particularly in beef breeds. Therefore, we performed a genome-wide association study using high-density genotypes to elucidate the genomic architecture of these traits and to identify regions of the bovine genome associated with them.

Results

Genomic regions associated with calving difficulty (direct and maternal) and perinatal mortality were detected using two statistical approaches: (1) single-SNP (single nucleotide polymorphism) regression and (2) a Bayesian approach. Data included high-density genotypes on 770 Holstein-Friesian, 927 Charolais and 963 Limousin bulls. Several novel or previously identified genomic regions were detected but associations differed by breed. For example, two genomic associations, one each on chromosomes 18 and 2 explained 2.49 % and 3.13 % of the genetic variance in direct calving difficulty in the Holstein-Friesian and Charolais populations, respectively. Imputed Holstein-Friesian sequence data was used to refine the genomic regions responsible for significant associations. Several candidate genes on chromosome 18 were identified and four highly significant missense variants were detected within three of these genes (SIGLEC12, CTU1, and ZNF615). Nevertheless, only CTU1 contained a missense variant with a putative impact on direct calving difficulty based on SIFT (0.06) and Polyphen (0.95) scores. Using imputed sequence data, we refined a genomic region on chromosome 4 associated with maternal calving difficulty in the Holstein-Friesian population and found the strongest association with an intronic variant in the PCLO gene. A meta-analysis was performed across the three breeds for each calving performance trait to identify common variants associated with these traits in the three breeds. Our results suggest that a portion of the genetic variation in calving performance is common to all three breeds.

Conclusion

The genomic architecture of calving performance is complex and mainly influenced by many polymorphisms of small effect. We identified several associations of moderate effect size but the majority were breed-specific, indicating that breed-specific alleles exist for calving performance or that the linkage phase between genotyped allele and causal mutation varies between breeds.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0126-4) contains supplementary material, which is available to authorized users.     

Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D

Background

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects.

Methods

We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis.

Results

We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis.

Conclusion

DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-011-0233-y) contains supplementary material, which is available to authorized users.     

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.     

Associations of single nucleotide polymorphisms in candidate genes with the polled trait in Datong domestic yaks

The domestic yak (Bos grunniens) is an iconic symbol of animal husbandry at high altitudes. Yaks exhibit unique external characteristics including long hair and large horns. However, hornless yaks can be found in different breeds and different populations. The hornless trait is also known as polled, and the POLL locus has been fine‐mapped to chromosome 1 in cattle (Bos taurus), although the underlying genetic basis of the polled trait is still unclear in the yak. Thus, we performed an association study to identify the genetic polymorphisms responsible for the polled trait in the yak. Fifty polled Datong domestic yaks and 51 horned individuals were selected randomly from a huge herd and were used as the case and control groups respectively for the association analysis. Twelve genes located in the candidate region of the POLL locus in cattle were used as references to detect DNA polymorphisms related to yak polledness, which were analyzed by sequencing and a high‐resolution melting test. We applied Fisher's exact test and haplotype analysis to show that a 147‐kb segment that included three protein‐coding genes C1H21orf62, GCFC1 and SYNJ1 was the most likely location of the POLL mutation in domestic yaks.     

Fine mapping of the polled locus to a 1-Mb region on bovine Chromosome 1q12

The absence of horns in Bos taurus is under genetic control of the autosomal dominant polled locus which has been genetically mapped to the centromeric region of cattle Chromosome 1. Recently a 4-Mb BAC contig of this chromosomal region has been constructed. Toward positional cloning of the bovine polled locus, we identified 20 additional microsatellite markers spread over the contig map by random sequencing of bacterial artificial chromosome (BAC) subclones. A total of 26 markers were genotyped in 30 two-generation half-sib families of six different German cattle breeds segregating for the hornless phenotype including 336 informative meioses for the polled character. Our fine-mapping study involving 19 recombinant haplotypes allowed us to narrow the critical region for the bovine polled locus to a 1-Mb segment with a centromeric boundary at RP42-218J17_MS1 and a telomeric boundary at BM6438. For marker-assisted selection purposes, the first evidence of informative flanking markers helps to predict polled genotypes with a higher degree of accuracy within families until testing of the causative mutation is available.     

Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds

Background

The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants.

Results

We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves.

Conclusions

We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1702-2) contains supplementary material, which is available to authorized users.     

Selection of haplotype variables from a high-density marker map for genomic prediction

Background

Using haplotype blocks as predictors rather than individual single nucleotide polymorphisms (SNPs) may improve genomic predictions, since haplotypes are in stronger linkage disequilibrium with the quantitative trait loci than are individual SNPs. It has also been hypothesized that an appropriate selection of a subset of haplotype blocks can result in similar or better predictive ability than when using the whole set of haplotype blocks. This study investigated genomic prediction using a set of haplotype blocks that contained the SNPs with large effects estimated from an individual SNP prediction model. We analyzed protein yield, fertility and mastitis of Nordic Holstein cattle, and used high-density markers (about 770k SNPs). To reach an optimum number of haplotype variables for genomic prediction, predictions were performed using subsets of haplotype blocks that contained a range of 1000 to 50 000 main SNPs.

Results

The use of haplotype blocks improved the prediction reliabilities, even when selection focused on only a group of haplotype blocks. In this case, the use of haplotype blocks that contained the 20 000 to 50 000 SNPs with the highest effect was sufficient to outperform the model that used all individual SNPs as predictors (up to 1.3 % improvement in prediction reliability for mastitis, compared to individual SNP approach), and the achieved reliabilities were similar to those using all haplotype blocks available in the genome data (from 0.6 % lower to 0.8 % higher reliability).

Conclusions

Haplotype blocks used as predictors can improve the reliability of genomic prediction compared to the individual SNP model. Furthermore, the use of a subset of haplotype blocks that contains the main SNP effects from genomic data could be a feasible approach to genomic prediction in dairy cattle, given an increase in density of genotype data available. The predictive ability of the models that use a subset of haplotype blocks was similar to that obtained using either all haplotype blocks or all individual SNPs, with the benefit of having a much lower computational demand.     

Genomic prediction using imputed whole-genome sequence data in Holstein Friesian cattle

Background

In contrast to currently used single nucleotide polymorphism (SNP) panels, the use of whole-genome sequence data is expected to enable the direct estimation of the effects of causal mutations on a given trait. This could lead to higher reliabilities of genomic predictions compared to those based on SNP genotypes. Also, at each generation of selection, recombination events between a SNP and a mutation can cause decay in reliability of genomic predictions based on markers rather than on the causal variants. Our objective was to investigate the use of imputed whole-genome sequence genotypes versus high-density SNP genotypes on (the persistency of) the reliability of genomic predictions using real cattle data.

Methods

Highly accurate phenotypes based on daughter performance and Illumina BovineHD Beadchip genotypes were available for 5503 Holstein Friesian bulls. The BovineHD genotypes (631,428 SNPs) of each bull were used to impute whole-genome sequence genotypes (12,590,056 SNPs) using the Beagle software. Imputation was done using a multi-breed reference panel of 429 sequenced individuals. Genomic estimated breeding values for three traits were predicted using a Bayesian stochastic search variable selection (BSSVS) model and a genome-enabled best linear unbiased prediction model (GBLUP). Reliabilities of predictions were based on 2087 validation bulls, while the other 3416 bulls were used for training.

Results

Prediction reliabilities ranged from 0.37 to 0.52. BSSVS performed better than GBLUP in all cases. Reliabilities of genomic predictions were slightly lower with imputed sequence data than with BovineHD chip data. Also, the reliabilities tended to be lower for both sequence data and BovineHD chip data when relationships between training animals were low. No increase in persistency of prediction reliability using imputed sequence data was observed.

Conclusions

Compared to BovineHD genotype data, using imputed sequence data for genomic prediction produced no advantage. To investigate the putative advantage of genomic prediction using (imputed) sequence data, a training set with a larger number of individuals that are distantly related to each other and genomic prediction models that incorporate biological information on the SNPs or that apply stricter SNP pre-selection should be considered.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0149-x) contains supplementary material, which is available to authorized users.     

Detection of selection signatures in dairy and beef cattle using high-density genomic information

Background

Artificial selection for economically important traits in cattle is expected to have left distinctive selection signatures on the genome. Access to high-density genotypes facilitates the accurate identification of genomic regions that have undergone positive selection. These findings help to better elucidate the mechanisms of selection and to identify candidate genes of interest to breeding programs.

Results

Information on 705 243 autosomal single nucleotide polymorphisms (SNPs) in 3122 dairy and beef male animals from seven cattle breeds (Angus, Belgian Blue, Charolais, Hereford, Holstein-Friesian, Limousin and Simmental) were used to detect selection signatures by applying two complementary methods, integrated haplotype score (iHS) and global fixation index (F_ST). To control for false positive results, we used false discovery rate (FDR) adjustment to calculate adjusted iHS within each breed and the genome-wide significance level was about 0.003. Using the iHS method, 83, 92, 91, 101, 85, 101 and 86 significant genomic regions were detected for Angus, Belgian Blue, Charolais, Hereford, Holstein-Friesian, Limousin and Simmental cattle, respectively. None of these regions was common to all seven breeds. Using the F_ST approach, 704 individual SNPs were detected across breeds. Annotation of the regions of the genome that showed selection signatures revealed several interesting candidate genes i.e. DGAT1, ABCG2, MSTN, CAPN3, FABP3, CHCHD7, PLAG1, JAZF1, PRKG2, ACTC1, TBC1D1, GHR, BMP2, TSG1, LYN, KIT and MC1R that play a role in milk production, reproduction, body size, muscle formation or coat color. Fifty-seven common candidate genes were found by both the iHS and global F_ST methods across the seven breeds. Moreover, many novel genomic regions and genes were detected within the regions that showed selection signatures; for some candidate genes, signatures of positive selection exist in the human genome. Multilevel bioinformatic analyses of the detected candidate genes suggested that the PPAR pathway may have been subjected to positive selection.

Conclusions

This study provides a high-resolution bovine genomic map of positive selection signatures that are either specific to one breed or common to a subset of the seven breeds analyzed. Our results will contribute to the detection of functional candidate genes that have undergone positive selection in future studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0127-3) contains supplementary material, which is available to authorized users.     

A missense mutation in the agouti signaling protein gene (ASIP) is associated with the no light points coat phenotype in donkeys

Background

Seven donkey breeds are recognized by the French studbook and are characterized by a black, bay or grey coat colour including light cream-to-white points (LP). Occasionally, Normand bay donkeys give birth to dark foals that lack LP and display the no light points (NLP) pattern. This pattern is more frequent and officially recognized in American miniature donkeys. The LP (or pangare) phenotype resembles that of the light bellied agouti pattern in mouse, while the NLP pattern resembles that of the mammalian recessive black phenotype; both phenotypes are associated with the agouti signaling protein gene (ASIP).

Findings

We used a panel of 127 donkeys to identify a recessive missense c.349 T > C variant in ASIP that was shown to be in complete association with the NLP phenotype. This variant results in a cysteine to arginine substitution at position 117 in the ASIP protein. This cysteine is highly-conserved among vertebrate ASIP proteins and was previously shown by mutagenesis experiments to lie within a functional site. Altogether, our results strongly support that the identified mutation is causative of the NLP phenotype.

Conclusions

Thus, we propose to name the c.[349 T > C] allele in donkeys, the a^nlp allele, which enlarges the panel of coat colour alleles in donkeys and ASIP recessive loss-of-function alleles in animals.

Electronic supplementary material

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Local genealogies in a linear mixed model for genome-wide association mapping in complex pedigreed populations

Introduction

The state-of-the-art for dealing with multiple levels of relationship among the samples in genome-wide association studies (GWAS) is unified mixed model analysis (MMA). This approach is very flexible, can be applied to both family-based and population-based samples, and can be extended to incorporate other effects in a straightforward and rigorous fashion. Here, we present a complementary approach, called ‘GENMIX (genealogy based mixed model)’ which combines advantages from two powerful GWAS methods: genealogy-based haplotype grouping and MMA.

Subjects and Methods

We validated GENMIX using genotyping data of Danish Jersey cattle and simulated phenotype and compared to the MMA. We simulated scenarios for three levels of heritability (0.21, 0.34, and 0.64), seven levels of MAF (0.05, 0.10, 0.15, 0.20, 0.25, 0.35, and 0.45) and five levels of QTL effect (0.1, 0.2, 0.5, 0.7 and 1.0 in phenotypic standard deviation unit). Each of these 105 possible combinations (3 h² x 7 MAF x 5 effects) of scenarios was replicated 25 times.

Results

GENMIX provides a better ranking of markers close to the causative locus'' location. GENMIX outperformed MMA when the QTL effect was small and the MAF at the QTL was low. In scenarios where MAF was high or the QTL affecting the trait had a large effect both GENMIX and MMA performed similarly.

Conclusion

In discovery studies, where high-ranking markers are identified and later examined in validation studies, we therefore expect GENMIX to enrich candidates brought to follow-up studies with true positives over false positives more than the MMA would.     

Autosomal Recessive Transmission of MYBPC3 Mutation Results in Malignant Phenotype of Hypertrophic Cardiomyopathy

Background

Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.

Methods

A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.

Results

A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.

Conclusions

Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.     

Predicting haplotype carriers from SNP genotypes in Bos taurus through linear discriminant analysis

Background

SNP (single nucleotide polymorphisms) genotype data are increasingly available in cattle populations and, among other things, can be used to predict carriers of specific haplotypes. It is therefore convenient to have a practical statistical method for the accurate classification of individuals into carriers and non-carriers. In this paper, we present a procedure combining variable selection (i.e. the selection of predictive SNPs) and linear discriminant analysis for the identification of carriers of a haplotype on BTA19 (Bos taurus autosome 19) known to be associated with reduced cow fertility. A population of 3645 Brown Swiss cows and bulls genotyped with the 54K SNP-chip was available for the analysis.

Results

The overall error rate for the prediction of haplotype carriers was on average very low (∼≤1%). The error rate was found to depend on the number of SNPs in the model and their density around the region of the haplotype on BTA19. The minimum set of SNPs to still achieve accurate predictions was 5, with a total test error rate of 1.59.

Conclusions

The paper describes a procedure to accurately identify haplotype carriers from SNP genotypes in cattle populations. Very few misclassifications were observed, which indicates that this is a very reliable approach for potential applications in cattle breeding.