Fine-mapping QTL for mastitis resistance on BTA9 in three Nordic red cattle breeds

A QTL affecting clinical mastitis and/or somatic cell score (SCS) has been reported previously on chromosome 9 from studies in 16 families from the Swedish Red and White (SRB), Finnish Ayrshire (FA) and Danish Red (DR) breeds. In order to refine the QTL location, 67 markers were genotyped over the whole chromosome in the 16 original families and 18 additional half-sib families. This enabled linkage disequilibrium information to be used in the analysis. Data were analysed by an approach that combines information from linkage and linkage disequilibrium, which allowed the QTL affecting clinical mastitis to be mapped to a small interval (<1 cM) between the markers BM4208 and INRA084 . This QTL showed a pleiotropic effect on SCS in the DR and SRB breeds. Haplotypes associated with variations in mastitis resistance were identified. The haplotypes were predictive in the general population and can be used in marker-assisted selection. Pleiotropic effects of the mastitis QTL were studied for three milk production traits and eight udder conformation traits. This QTL was also associated with yield traits in DR but not in FA or SRB. No QTL were found for udder conformation traits on chromosome 9.     

The origin of selection signatures on bovine chromosome 6

The extent and pattern of linkage disequilibrium (LD) between closely spaced markers contain information about population history, including past population size and selection history. Selection signatures can be identified by comparing the LD surrounding a putative selected allele at a locus to the putative non-selected allele. In livestock populations, locations of selection signatures identified in this way should be correlated with QTL affecting production traits, as the populations have been under strong artificial selection for these traits. We used a dense SNP map of bovine chromosome 6 to characterize the pattern of LD on this chromosome in Norwegian Red cattle, a breed which has been strongly selected for milk production. The pattern of LD was generally consistent with strong selection in regions containing QTL affecting milk production traits, including a strong selection signature in a region containing a mutation known to affect milk production. The results demonstrate that in livestock populations, the origin of selection signatures will often be QTL for livestock production traits, and illustrate the value of selection signatures in uncovering new mutations with potential effects on quantitative traits.     

Mapping of a milk production quantitative trait locus to a 420-kb region on bovine chromosome 6

A QTL affecting milk production traits was previously mapped to an interval of 7.5 cM on chromosome 6 in Norwegian dairy cattle. This article aimed to refine this position by increasing the map density in the region by a set of single-nucleotide polymorphisms and analyzing the data with a combined linkage and linkage disequilibrium approach. Through a series of single- and multitrait and single- and multipoint analyses, the QTL was positioned to an interval surrounded by the genes ABCG2 and LAP3. As no recombinations were detected in this interval, physical mapping was required for further refining. By using radiation hybrid mapping as well as BAC clones, the bovine and human comparative maps in the region are resolved, and the QTL is mapped within a distance of 420 kb.     

Mapping multiple QTL using linkage disequilibrium and linkage analysis information and multitrait data

A multi-locus QTL mapping method is presented, which combines linkage and linkage disequilibrium (LD) information and uses multitrait data. The method assumed a putative QTL at the midpoint of each marker bracket. Whether the putative QTL had an effect or not was sampled using Markov chain Monte Carlo (MCMC) methods. The method was tested in dairy cattle data on chromosome 14 where the DGAT1 gene was known to be segregating. The DGAT1 gene was mapped to a region of 0.04 cM, and the effects of the gene were accurately estimated. The fitting of multiple QTL gave a much sharper indication of the QTL position than a single QTL model using multitrait data, probably because the multi-locus QTL mapping reduced the carry over effect of the large DGAT1 gene to adjacent putative QTL positions. This suggests that the method could detect secondary QTL that would, in single point analyses, remain hidden under the broad peak of the dominant QTL. However, no indications for a second QTL affecting dairy traits were found on chromosome 14.     

The X chromosome in quantitative trait locus mapping

The X chromosome requires special treatment in the mapping of quantitative trait loci (QTL). However, most QTL mapping methods, and most computer programs for QTL mapping, have focused exclusively on autosomal loci. We describe a method for appropriate treatment of the X chromosome for QTL mapping in experimental crosses. We address the important issue of formulating the null hypothesis of no linkage appropriately. If the X chromosome is treated like an autosome, a sex difference in the phenotype can lead to spurious linkage on the X chromosome. Further, the number of degrees of freedom for the linkage test may be different for the X chromosome than for autosomes, and so an X chromosome-specific significance threshold is required. To address this issue, we propose a general procedure to obtain chromosome-specific significance thresholds that controls the genomewide false positive rate at the desired level. We apply our methods to data on gut length in a large intercross of mice carrying the Sox10Dom mutation, a model of Hirschsprung disease. We identified QTL contributing to variation in gut length on chromosomes 5 and 18. We found suggestive evidence of linkage to the X chromosome, which would be viewed as strong evidence of linkage if the X chromosome was treated as an autosome. Our methods have been implemented in the package R/qtl.     

Refining the genetic portrait of Portuguese Roma through X-chromosomal markers

Due to differences in transmission between X-chromosomal and autosomal DNA, the comparison of data derived from both markers allows deeper insight into the forces that shape the patterns of genetic diversity in populations. In this study, we applied this comparative approach to a sample of Portuguese Roma (Gypsies) by analyzing 43 X-chromosomal markers and 53 autosomal markers. Portuguese individuals of non-Gypsy ancestry were also studied. Compared with the host population, reduced levels of diversity on the X chromosome and autosomes were detected in Gypsies; this result was in line with known patterns of genetic diversity typical of Roma groups. As a consequence of the complex demographic past of the Roma, during which admixture and genetic drift played major roles, the amount of linkage disequilibrium (LD) on the X chromosome in Gypsies was considerably higher than that observed in non-Gypsies. When the pattern of differentiation on the X chromosome was compared with that of autosomes, there was evidence for asymmetries in female and male effective population sizes during the admixture between Roma and non-Roma. This result supplements previous data provided by mtDNA and the Y chromosome, underlining the importance of using combined information from the X chromosome and autosomes to dissect patterns of genetic diversity. Following the out-of-India dispersion, the Roma acquired a complex genetic pattern that was influenced by drift and introgression with surrounding populations, with important contributions from both males and females. We provide evidence that a sex-biased admixture with Europeans is probably associated with the founding of the Portuguese Gypsies.     

Fine mapping of quantitative trait loci for mastitis resistance on bovine chromosome 11

Quantitative trait loci (QTL) affecting clinical mastitis (CM) and somatic cell score (SCS) were mapped on bovine chromosome 11. The mapping population consisted of 14 grandsire families belonging to three Nordic red cattle breeds: Finnish Ayrshire (FA), Swedish Red and White (SRB) and Danish Red. The families had previously been shown to segregate for udder health QTL. A total of 524 progeny tested bulls were included in the analysis. A linkage map including 33 microsatellite and five SNP markers was constructed. We performed combined linkage disequilibrium and linkage analysis (LDLA) using the whole data set. Further analyses were performed for FA and SRB separately to study the origin of the identified QTL/haplotype and to examine if it was common in both populations. Finally, different two-trait models were fitted. These postulated either a pleiotropic QTL affecting both traits; two linked QTL, each affecting one trait; or one QTL affecting a single trait. A QTL affecting CM was fine-mapped. In FA, a haplotype having a strong association with a high negative effect on mastitis resistance was identified. The mapping precision of an earlier detected SCS-QTL was not improved by the LDLA analysis because of lack of linkage disequilibrium between the markers used and the QTL in the region.     

Mapping of QTL for Body Conformation and Behavior in Cattle

Genome scans for quantitative trait loci (QTL) in farm animals have concentrated on primary production and health traits, and information on QTL for other important traits is rare. We performed a whole genome scan in a granddaughter design to detect QTL affecting body conformation and behavior in dairy cattle. The analysis included 16 paternal half-sib families of the Holstein breed with 872 sons and 264 genetic markers. The markers were distributed across all 29 autosomes and the pseudoautosomal region of the sex chromosomes with average intervals of 13.9 cM and covering an estimated 3155.5 cM. All families were analyzed jointly for 22 traits using multimarker regression and significance thresholds determined empirically by permutation. QTL that exceeded the experiment-wise significance threshold (5% level) were detected on chromosome 6 for foot angle, teat placement, and udder depth, and on chromosome 29 for temperament. QTL approaching experiment-wise significance (10% level) were located on chromosome 6 for general quality of feet and legs and general quality of udder, on chromosome 13 for teat length, on chromosome 23 for general quality of feet and legs, and on chromosome 29 for milking speed. An additional 51 QTL significant at the 5% chromosome-wise level were distributed over 21 chromosomes. This study provides the first evidence for QTL involved in behavior of dairy cattle and identifies QTL for udder conformation on chromosome 6 that could form the basis of recently reported QTL for clinical mastitis.     

Confirmation and fine‐mapping of clinical mastitis and somatic cell score QTL in Nordic Holstein cattle

A genome‐wide association study of 2098 progeny‐tested Nordic Holstein bulls genotyped for 36 387 SNPs on 29 autosomes was conducted to confirm and fine‐map quantitative trait loci (QTL) for mastitis traits identified earlier using linkage analysis with sparse microsatellite markers in the same population. We used linear mixed model analysis where a polygenic genetic effect was fitted as a random effect and single SNPs were successively included as fixed effects in the model. We detected 143 SNP‐by‐trait significant associations (P < 0.0001) on 20 chromosomes affecting mastitis‐related traits. Among them, 21 SNP‐by‐trait combinations exceeded the genome‐wide significant threshold. For 12 chromosomes, both the present association study and the previous linkage study detected QTL, and of these, six were in the same chromosomal locations. Strong associations of SNPs with mastitis traits were observed on bovine autosomes 6, 13, 14 and 20. Possible candidate genes for these QTL were identified. Identification of SNPs in linkage disequilibrium with QTL will enable marker‐based selection for mastitis resistance. The candidate genes identified should be further studied to detect candidate polymorphisms underlying these QTL.     

Contrasting results from GWAS and QTL mapping on wing length in great reed warblers

A major goal in evolutionary biology is to understand the genetic basis of adaptive traits. In migratory birds, wing morphology is such a trait. Our previous work on the great reed warbler (Acrocephalus arundinaceus) shows that wing length is highly heritable and under sexually antagonistic selection. Moreover, a quantitative trait locus (QTL) mapping analysis detected a pronounced QTL for wing length on chromosome 2, suggesting that wing morphology is partly controlled by genes with large effects. Here, we re‐evaluate the genetic basis of wing length in great reed warblers using a genomewide association study (GWAS) approach based on restriction site‐associated DNA sequencing (RADseq) data. We use GWAS models that account for relatedness between individuals and include covariates (sex, age and tarsus length). The resulting association landscape was flat with no peaks on chromosome 2 or elsewhere, which is in line with expectations for polygenic traits. Analysis of the distribution of p‐values did not reveal biases, and the inflation factor was low. Effect sizes were however not uniformly distributed on some chromosomes, and the Z chromosome had weaker associations than autosomes. The level of linkage disequilibrium (LD) in the population decayed to background levels within c. 1 kbp. There could be several reasons to why our QTL study and GWAS gave contrasting results including differences in how associations are modelled (cosegregation in pedigree vs. LD associations), how covariates are accounted for in the models, type of marker used (multi‐ vs. biallelic), difference in power or a combination of these. Our study highlights that the genetic architecture even of highly heritable traits is difficult to characterize in wild populations.     

GWA Analysis for Milk Production Traits in Dairy Sheep and Genetic Support for a QTN Influencing Milk Protein Percentage in the LALBA Gene

In this study, we used the Illumina OvineSNP50 BeadChip to conduct a genome-wide association (GWA) analysis for milk production traits in dairy sheep by analyzing a commercial population of Spanish Churra sheep. The studied population consisted of a total of 1,681 Churra ewes belonging to 16 half-sib families with available records for milk yield (MY), milk protein and fat yields (PY and FY) and milk protein and fat contents (PP and FP). The most significant association identified reached experiment-wise significance for PP and FP and was located on chromosome 3 (OAR3). These results confirm the population-level segregation of a previously reported QTL affecting PP and suggest that this QTL has a significant pleiotropic effect on FP. Further associations were detected at the chromosome-wise significance level on 14 other chromosomal regions. The marker on OAR3 showing the highest significant association was located at the third intron of the alpha-lactalbumin (LALBA) gene, which is a functional and positional candidate underlying this association. Sequencing this gene in the 16 Churra rams of the studied resource population identified additional polymorphisms. One out of the 31 polymorphisms identified was located within the coding gene sequence (LALBA_g.242T>C) and was predicted to cause an amino acid change in the protein (Val27Ala). Different approaches, including GWA analysis, a combined linkage and linkage disequilibrium study and a concordance test with the QTL segregating status of the sires, were utilized to assess the role of this mutation as a putative QTN for the genetic effects detected on OAR3. Our results strongly support the polymorphism LALBA_g.242T>C as the most likely causal mutation of the studied OAR3 QTL affecting PP and FP, although we cannot rule out the possibility that this SNP is in perfect linkage disequilibrium with the true causal polymorphism.     

Fine mapping and physical characterization of two linked quantitative trait loci affecting milk fat yield in dairy cattle on BTA26

Previously, a highly significant QTL affecting fat yield and protein yield and mapped to the bovine BTA26 chromosome has been reported to segregate in the French Holstein cattle population. To confirm and refine the location of this QTL, the original detection experiment was extended by adding 12 new families and genotyping 25 additional microsatellite markers (including 11 newly developed markers). Data were then analyzed by an approach combining both linkage and linkage disequilibrium information, making it possible to identify two linked QTL separated by 20 cM corresponding to approximately 29 Mb. The presence of a QTL affecting protein yield was confirmed but its position was found to be more telomeric than the two QTLunderlying fat yield. Each identified QTL affecting milk fat yield was physically mapped within a segment estimated to be <500 kb. Two strong functional candidate genes involved, respectively, in fatty acid metabolism and membrane permeability were found to be localized within this segment while other functional candidate genes were discarded. A haplotype comprising the favorable allele at each QTL position appears to be overrepresented in the artificial insemination bull population.     

Characterization of the porcine FABP5 gene and its association with the FAT1 QTL in an Iberian by Landrace cross

We have characterized and mapped the porcine fatty acid binding protein 5, epidermal (FABP5) gene. According to linkage and RH mapping, this gene is located close to the FABP4 (fatty acid binding protein 4, adipocyte) gene on swine chromosome 4. We resequenced 4.7 kb of the FABP5 gene in the parental population of an Iberian x Landrace cross (IBMAP), identifying seven SNPs arranged in two distinct FABP5 haplotypes. QTL and association analyses in the IBMAP population showed that this gene is strongly associated with fat deposition. QTL and haplotype analysis revealed that both FABP4 and FABP5 (clustered in mammals) are major candidate genes for the FAT1 QTL; the most likely position for the FAT1 QTL is between these two genes. Finally, our results suggest the presence of more than one QTL affecting fatness traits on porcine chromosome 4.     

A transmission/disequilibrium test approach to screen for quantitative trait loci in two selected lines of large white pigs

Pedigree and marker data from a multiple-generation pig selection experiment have been analysed to screen for loci affecting quantitative traits (QTL). Pigs from a base population were selected either for low backfat thickness at fixed live weight (L-line) or high live weight at fixed age (F-line). Selection was based on single-trait own performance and DNA was available on selected individuals only. Genotypes for three marker loci with known positions on chromosome 4 were available. The transmission/disequilibrium test (TDT) was originally described in human genetics to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Here, we adapt the TDT to test for linkage between a marker and QTL favoured by selection, and for linkage disequilibrium between them in the base population. The a priori unknown distribution of the test statistic under the null hypothesis, no linkage, was obtained via Monte Carlo simulation. Significant TDT statistics were found for markers AFABP and SW818 in the F-line, indicating the presence of a closely linked QTL affecting growth performance. In the L-line, none of the markers studied showed significance. This study emphasizes the potential of the TDT as a quick and simple approach to screen for QTL in situations where marker genotypes are available on selected individuals. The results suggest that previously identified QTL in crosses of genetically diverse breeds may also segregate in commercial selection lines.     

Genome-wide association mapping of agronomic traits in sugar beet

Recent results indicate that association mapping in populations from applied plant breeding is a powerful tool to detect QTL which are of direct relevance for breeding. The focus of this study was to unravel the genetic architecture of six agronomic traits in sugar beet. To this end, we employed an association mapping approach, based on a very large population of 924 elite sugar beet lines from applied plant breeding, fingerprinted with 677 single nucleotide polymorphism (SNP) markers covering the entire genome. We show that in this population linkage disequilibrium decays within a short genetic distance and is sufficient for the detection of QTL with a large effect size. To increase the QTL detection power and the mapping resolution a much higher number of SNPs is required. We found that for QTL detection, the mixed model including only the kinship matrix performed best, even in the presence of a considerable population structure. In genome-wide scans, main effect QTL and epistatic QTL were detected for all six traits. Our full two-dimensional epistasis scan revealed that for complex traits there appear to be epistatic master regulators, loci which are involved in a large number of epistatic interactions throughout the genome.     

An apparent excess of sex- and reproduction-related genes on the human X chromosome

We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose-dependent processes, the number of such genes necessary to be regulated in a dose-dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian-marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage.     

Genome-wide association mapping of yield and yield components of spring wheat under contrasting moisture regimes

Key message

A stable QTL that may be used in marker-assisted selection in wheat breeding programs was detected for yield, yield components and drought tolerance-related traits in spring wheat association mapping panel.

Abstract

Genome-wide association mapping has become a widespread method of quantitative trait locus (QTL) identification for many crop plants including wheat (Triticum aestivum L.). Its benefit over traditional bi-parental mapping approaches depends on the extent of linkage disequilibrium in the mapping population. The objectives of this study were to determine linkage disequilibrium decay rate and population structure in a spring wheat association mapping panel (n = 285–294) and to identify markers associated with yield and yield components, morphological, phenological, and drought tolerance-related traits. The study was conducted under fully irrigated and rain-fed conditions at Greeley, CO, USA and Melkassa, Ethiopia in 2010 and 2011 (five total environments). Genotypic data were generated using diversity array technology markers. Linkage disequilibrium decay rate extended over a longer genetic distance for the D genome (6.8 cM) than for the A and B genomes (1.7 and 2.0 cM, respectively). Seven subpopulations were identified with population structure analysis. A stable QTL was detected for grain yield on chromosome 2DS both under irrigated and rain-fed conditions. A multi-trait region significant for yield and yield components was found on chromosome 5B. Grain yield QTL on chromosome 1BS co-localized with harvest index QTL. Vegetation indices shared QTL with harvest index on chromosome 1AL and 5A. After validation in relevant genetic backgrounds and environments, QTL detected in this study for yield, yield components and drought tolerance-related traits may be used in marker-assisted selection in wheat breeding programs.     

Quantitative trait loci linked to PRNP gene controlling health and production traits in INRA 401 sheep

In this study, the potential association of PrP genotypes with health and productive traits was investigated. Data were recorded on animals of the INRA 401 breed from the Bourges-La Sapinière INRA experimental farm. The population consisted of 30 rams and 852 ewes, which produced 1310 lambs. The animals were categorized into three PrP genotype classes: ARR homozygous, ARR heterozygous, and animals without any ARR allele. Two analyses differing in the approach considered were carried out. Firstly, the potential association of the PrP genotype with disease (Salmonella resistance) and production (wool and carcass) traits was studied. The data used included 1042, 1043 and 1013 genotyped animals for the Salmonella resistance, wool and carcass traits, respectively. The different traits were analyzed using an animal model, where the PrP genotype effect was included as a fixed effect. Association analyses do not indicate any evidence of an effect of PrP genotypes on traits studied in this breed. Secondly, a quantitative trait loci (QTL) detection approach using the PRNP gene as a marker was applied on ovine chromosome 13. Interval mapping was used. Evidence for one QTL affecting mean fiber diameter was found at 25 cM from the PRNP gene. However, a linkage between PRNP and this QTL does not imply unfavorable linkage disequilibrium for PRNP selection purposes.     

Joint linkage and linkage disequilibrium mapping of quantitative trait loci in natural populations

Linkage analysis and allelic association (also referred to as linkage disequilibrium) studies are two major approaches for mapping genes that control simple or complex traits in plants, animals, and humans. But these two approaches have limited utility when used alone, because they use only part of the information that is available for a mapping population. More recently, a new mapping strategy has been designed to integrate the advantages of linkage analysis and linkage disequilibrium analysis for genome mapping in outcrossing populations. The new strategy makes use of a random sample from a panmictic population and the open-pollinated progeny of the sample. In this article, we extend the new strategy to map quantitative trait loci (QTL), using molecular markers within the EM-implemented maximum-likelihood framework. The most significant advantage of this extension is that both linkage and linkage disequilibrium between a marker and QTL can be estimated simultaneously, thus increasing the efficiency and effectiveness of genome mapping for recalcitrant outcrossing species. Simulation studies are performed to test the statistical properties of the MLEs of genetic and genomic parameters including QTL allele frequency, QTL effects, QTL position, and the linkage disequilibrium of the QTL and a marker. The potential utility of our mapping strategy is discussed.     

Genetic control of X chromosome inactivation in mice: definition of the Xce candidate interval

In early mammalian development, one of the two X chromosomes is silenced in each female cell as a result of X chromosome inactivation, the mammalian dosage compensation mechanism. In the mouse epiblast, the choice of which chromosome is inactivated is essentially random, but can be biased by alleles at the X-linked X controlling element (Xce). Although this locus was first described nearly four decades ago, the identity and precise genomic localization of Xce remains elusive. Within the X inactivation center region of the X chromosome, previous linkage disequilibrium studies comparing strains of known Xce genotypes have suggested that Xce is physically distinct from Xist, although this has not yet been established by genetic mapping or progeny testing. In this report, we used quantitative trait locus (QTL) mapping strategies to define the minimal Xce candidate interval. Subsequent analysis of recombinant chromosomes allowed for the establishment of a maximum 1.85-Mb candidate region for the Xce locus. Finally, we use QTL approaches in an effort to identify additional modifiers of the X chromosome choice, as we have previously demonstrated that choice in Xce heterozygous females is significantly influenced by genetic variation present on autosomes (Chadwick and Willard 2005). We did not identify any autosomal loci with significant associations and thus show conclusively that Xce is the only major locus to influence X inactivation patterns in the crosses analyzed. This study provides a foundation for future analyses into the genetic control of X chromosome inactivation and defines a 1.85-Mb interval encompassing all the major elements of the Xce locus.