Large-effect pleiotropic or closely linked QTL segregate within and across ten US cattle breeds

Background

The availability of high-density SNP assays including the BovineSNP50 (50 K) enables the identification of novel quantitative trait loci (QTL) and improvement of the resolution of the locations of previously mapped QTL. We performed a series of genome-wide association studies (GWAS) using 50 K genotypes scored in 18,274 animals from 10 US beef cattle breeds with observations for twelve body weights, calving ease and carcass traits.

Results

A total of 159 large-effects QTL (defined as 1-Mb genome windows explaining more than 1% of additive genetic variance) were identified. In general, more QTL were identified in analyses with bigger sample sizes. Four large-effect pleiotropic or closely linked QTLs located on BTA6 at 37–42 Mb (primarily at 38 Mb), on BTA7 at 93 Mb, on BTA14 at 23–26 Mb (primarily at 25 Mb) and on BTA20 at 4 Mb were identified in more than one breed. Several breed-specific large-effect pleiotropic or closely linked QTL were also identified. Some identified QTL regions harbor genes known to have large effects on a variety of traits in cattle such as PLAG1 and MSTN and others harbor promising candidate genes including NCAPG, ARRDC3, ERGIC1, SH3PXD2B, HMGA2, MSRB3, LEMD3, TIGAR, SEPT7, and KIRREL3. Gene ontology analysis revealed that genes involved in ossification and in adipose tissue development were over-represented in the identified pleiotropic QTL. Also, the MAPK signaling pathway was identified as a common pathway affected by the genes located near the pleiotropic QTL.

Conclusions

This largest GWAS ever performed in beef cattle, led us to discover several novel across-breed and breed-specific large-effect pleiotropic QTL that cumulatively account for a significant percentage of additive genetic variance (e.g. more than a third of additive genetic variance of birth and mature weights; and calving ease direct in Hereford). These results will improve our understanding of the biology of growth and body composition in cattle.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-442) contains supplementary material, which is available to authorized users.     

A genome‐wide association study suggests several novel candidate genes for carcass traits in Chinese Simmental beef cattle

A genome‐wide association study (GWAS) was conducted for two carcass traits in Chinese Simmental beef cattle. The experimental population consisted of 1301 individuals genotyped with the Illumina BovineHD SNP BeadChip (770K). After quality control, 671 990 SNPs and 1217 individuals were retained for the GWAS. The phenotypic traits included carcass weight and bone weight, which were measured after the cattle were slaughtered at 16 to 18 months of age. Three statistical models—a fixed polygene model, a random polygene model and a composite interval mapping polygene model—were used for the GWAS. The genome‐wide significance threshold after Bonferroni correction was 7.44E‐08 (= 0.05/671 990). In this study, we detected eight and seven SNPs significantly associated with carcass weight and bone weight respectively. In total, 11 candidate genes were identified within or close to these significant SNPs. Of these, we found several novel candidate genes, including PBX1, GCNT4, ALDH1A2, LCORL and WDFY3, to be associated with carcass weight and bone weight in Chinese Simmental beef cattle, and their functional roles need to be verified in further studies.     

Genome‐wide association study for body weight in cattle populations from Siberia

Body weight is a complex trait in cattle associated with commonly used commercial breeding measurements related to growth. Although many quantitative trait loci (QTL) for body weight have been identified in cattle so far, searching for genetic determinants in different breeds or environments is promising. Therefore, we carried out a genome‐wide association study (GWAS) in two cattle populations from the Russian Federation (Siberian region) using the GGP HD150K array containing 139 376 single nucleotide polymorphism (SNP) markers. Association tests for 107 550 SNPs left after filtering revealed five statistically significant SNPs on BTA5, considering a false discovery rate of less than 0.05. The chromosomal region containing these five SNPs contains the CCND2 gene, which was previously associated with average daily weight gain and body mass index in US beef cattle populations and in humans respectively. Our study is the first GWAS for body weight in beef cattle populations from the Russian Federation. The results provided here suggest that, despite the existence of breed‐ and species‐specific QTL, the genetic architecture of body weight could be evolutionarily conserved in mammals.     

Correlated Responses in Male Reproductive Traits in Mice Selected for Litter Size and Body Weight

Correlated responses in male reproductive traits were determined at 4, 6 and 8 weeks of age in lines of mice selected for large litter size (L⁺), large 6-week body weight (W⁺), large litter size and small body weight (L⁺W^-) and small litter size and large body weight (L^-W⁺), and in an unselected control (K). Concentration of serum testosterone and weights of testes, seminal vesicles, epididymides and adrenal glands increased with age. Line differences in testosterone concentration were not detected. L⁺ and W⁺ males exhibited positive correlated responses in testes, epididymides and seminal vescile weights. Testis weight adjusted for body weight was significantly larger for L⁺ than controls and approached significance for W⁺. Realized genetic correlation betestis weight and litter size was 0.60 ± 0.04, and the realized partial genetic correlation holding body weight constant was 0.42. Therefore, pleiotropic loci, acting via the hypothalamic-pituitary axis, affect testis weight and litter size independently of body weight. Additionally, genes influencing overall growth have a pleiotropic effect on testis weight and litter size in mice; the realized genetic correlations of body weight with testis weight and with litter size were 0.60 ± 0.03 and 0.52 ± 0.10. Testis weight increased in both L⁺W^- and L^-W⁺ males. The positive correlated response in L⁺W^- may have resulted from changes in frequency of genes controlling reproductive processes; whereas, in L^-W⁺ it could have been the result of changes in the frequency of genes associated with body weight.     

A genome-wide association study identifies genomic loci associated with backfat thickness,carcass weight,and body weight in two commercial pig populations

Growth and fatness traits are economically important in the pig industry. To dissect the genetic architecture of these traits in commercial pigs, we conducted a genome-wide association study (GWAS) for carcass weight, backfat thickness, and body weight in two commercial populations: Duroc × (Landrace × Yorkshire) (DLY) and Duroc populations. To enhance the detection power, three GWAS approaches including single-trait GWAS, multi-trait GWAS and meta-analysis were used in this study. A total of 13 suggestive loci were identified on nine chromosomes. The most significant locus was detected at 272.05 Mb on SSC1, and it was associated with backfat thickness at the first rib in the DLY population. Three genes at the identified loci (TBC1D1, BAAT and PHLPP1) were highlighted as functionally plausible candidate genes for pig growth and fatness traits. Genome-wide significant locus was not evidenced in this study, indicating that large populations are required to identify QTL with minor effects on growth and fatness traits in commercial pig populations, in which intensively artificial selections have been imposed on these traits and small genetical variances usually retain in these traits.     

Analysis of growth patterns in purebred Kambing Katjang goat and its crosses with the German Fawn

The objective of this study was to investigate growth patterns of goats utilizing data from a crossbreeding program involving the exotic German Fawn (GF) and the indigenous Kambing Katjang (KK) goats. Growth curve models and growth curve parameters were compared and analyzed for different genotypes and litter types. A total of 20,393 weight–age data from 208 female goats belonging to various crossbreeding genotypes were individually fitted to four growth curve models (Brody, Bertalanffy, Gompertz and Logistic). The goodness of fit was highest in the Brody model in most cases. A comparison of R² among genotypes showed that they were highest for KK. There were no significant differences of genotypes for estimated mature weight in the Brody model. The estimated mature weights for KK were significantly lower (P < 0.05) than for GF × KK (F₁), backcrosses with 75% GF genes (BC) and F₁ × F₁ (F₂) in the other models. The correlations between estimated mature weights and the maturing rates were lowest for BC. The genotype significantly (P < 0.01) affected the age at the constant degree of maturity (67% and 90% of mature weight) in all models. The BC genotype was the youngest at maturity and KK the oldest. All models well expressed the growth pattern of the target animals when they were older than 2.5 years of age. The results from the present study showed that the growth pattern may be altered by crossbreeding of KK with the GF breed.     

Effects of Feeding Selenium-Enriched Alfalfa Hay on Immunity and Health of Weaned Beef Calves

Previously, we reported that feeding selenium (Se)-enriched forage improves antibody titers in mature beef cows, and whole-blood Se concentrations and growth rates in weaned beef calves. Our current objective was to test whether beef calves fed Se-enriched alfalfa hay during the transition period between weaning and movement to a feedlot also have improved immune responses and slaughter weights. Recently weaned beef calves (n?=?60) were fed an alfalfa-hay-based diet for 7 weeks, which was harvested from fields fertilized with sodium selenate at 0, 22.5, 45.0, or 89.9 g Se/ha. All calves were immunized with J-5 Escherichia coli bacterin. Serum was collected for antibody titers 2 weeks after the third immunization. Whole-blood neutrophils collected at 6 or 7 weeks were evaluated for total antioxidant potential, bacterial killing activity, and expression of genes associated with selenoproteins and innate immunity. Calves fed the highest versus the lowest level of Se-enriched alfalfa hay had higher antibody titers (P?=?0.02), thioredoxin reductase-2 mRNA levels (P?=?0.07), and a greater neutrophil total antioxidant potential (P?=?0.10), whereas mRNA levels of interleukin-8 receptor (P?=?0.02), l-selectin (P?=?0.07), and thioredoxin reductase-1 (P?=?0.07) were lower. In the feedlot, calves previously fed the highest-Se forage had lower mortality (P?=?0.04) and greater slaughter weights (P?=?0.02). Our results suggest that, in areas with low-forage Se concentrations, feeding beef calves Se-enriched alfalfa hay during the weaning transition period improves vaccination responses and subsequent growth and survival in the feedlot.     

SNP markers associated with body size and pelt length in American mink (<Emphasis Type="Italic">Neovison vison</Emphasis>)

Background

Identification of genes underlying production traits is a key aim of the mink research community. Recent availability of genomic tools have opened the possibility for faster genetic progress in mink breeding. Availability of mink genome assembly allows genome-wide association studies in mink.

Results

In this study, we used genotyping-by-sequencing to obtain single nucleotide polymorphism (SNP) genotypes of 2496 mink. After multiple rounds of filtering, we retained 28,336 high quality SNPs and 2352 individuals for a genome-wide association study (GWAS). We performed the first GWAS for body weight, behavior, along with 10 traits related to fur quality in mink.

Conclusions

Combining association results with existing functional information of genes and mammalian phenotype databases, we proposed WWC3, MAP2K4, SLC7A1 and USP22 as candidate genes for body weight and pelt length in mink.

     

Fine-mapping alleles for body weight in LG/J �� SM/J F2 and F34 advanced intercross lines

The present study measured variation in body weight using a combined analysis in an F₂ intercross and an F₃₄ advanced intercross line (AIL). Both crosses were derived from inbred LG/J and SM/J mice, which were selected for large and small body size prior to inbreeding. Body weight was measured at 62 (±5) days of age. Using an integrated GWAS and forward model selection approach, we identified 11 significant QTLs that affected body weight on ten different chromosomes. With these results we developed a full model that explained over 18% of the phenotypic variance. The median 1.5-LOD support interval was 5.55 Mb, which is a significant improvement over most prior body weight QTLs. We identified nonsynonymous coding SNPs between LG/J and SM/J mice in order to further narrow the list of candidate genes. Three of the genes with nonsynonymous coding SNPs (Rad23b, Stk33, and Anks1b) have been associated with adiposity, waist circumference, and body mass index in human GWAS, thus providing evidence that these genes may underlie our QTLs. Our results demonstrate that a relatively small number of loci contribute significantly to the phenotypic variance in body weight, which is in marked contrast to the situation in humans. This difference is likely to be the result of strong selective pressure and the simplified genetic architecture, both of which are important advantages of our system.     

Genome-Wide Association for Growth Traits in Canchim Beef Cattle

Studies are being conducted on the applicability of genomic data to improve the accuracy of the selection process in livestock, and genome-wide association studies (GWAS) provide valuable information to enhance the understanding on the genetics of complex traits. The aim of this study was to identify genomic regions and genes that play roles in birth weight (BW), weaning weight adjusted for 210 days of age (WW), and long-yearling weight adjusted for 420 days of age (LYW) in Canchim cattle. GWAS were performed by means of the Generalized Quasi-Likelihood Score (GQLS) method using genotypes from the BovineHD BeadChip and estimated breeding values for BW, WW, and LYW. Data consisted of 285 animals from the Canchim breed and 114 from the MA genetic group (derived from crossings between Charolais sires and ½ Canchim + ½ Zebu dams). After applying a false discovery rate correction at a 10% significance level, a total of 4, 12, and 10 SNPs were significantly associated with BW, WW, and LYW, respectively. These SNPs were surveyed to their corresponding genes or to surrounding genes within a distance of 250 kb. The genes DPP6 (dipeptidyl-peptidase 6) and CLEC3B (C-type lectin domain family 3 member B) were highlighted, considering its functions on the development of the brain and skeletal system, respectively. The GQLS method identified regions on chromosome associated with birth weight, weaning weight, and long-yearling weight in Canchim and MA animals. New candidate regions for body weight traits were detected and some of them have interesting biological functions, of which most have not been previously reported. The observation of QTL reports for body weight traits, covering areas surrounding the genes (SNPs) herein identified provides more evidence for these associations. Future studies targeting these areas could provide further knowledge to uncover the genetic architecture underlying growth traits in Canchim cattle.     

Genome-wide association study reveals the genetic basis of growth trait in yellow catfish with sexual size dimorphism

Sexual size dimorphism has been widely observed in a large number of animals including fish species. Genome-wide association study (GWAS) is a powerful tool to dissect the genetic basis of complex traits, whereas the sex-differences in the genomics of animal complex traits have been ignored in the GWAS analysis. Yellow catfish (Pelteobagrus fulvidraco) is an important aquaculture fish in China with significant sexual size dimorphism. In this study, GWAS was conducted to identify candidate SNPs and genes related to body length (BL) and body weight (BW) in 125 female yellow catfish from a breeding population. In total, one BL-related SNP and three BW-related SNPs were identified to be significantly associated with the traits. Besides, one of these SNPs (Chr15:19195072) was shared in both the BW and BL traits in female yellow catfish, which was further validated in 185 male individuals and located on the exon of stat5b gene. Transgenic yellow catfish and zebrafish that expressed yellow catfish stat5b showed increased growth rate and reduction of sexual size dimorphism. These results not only reveal the genetic basis of growth trait and sexual size dimorphism in fish species, but also provide useful information for the marker-assisted breeding in yellow catfish.     

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10^?6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.     

QTLs associated with dry matter intake,metabolic mid-test weight,growth and feed efficiency have little overlap across 4 beef cattle studies

Background

The identification of genetic markers associated with complex traits that are expensive to record such as feed intake or feed efficiency would allow these traits to be included in selection programs. To identify large-effect QTL, we performed a series of genome-wide association studies and functional analyses using 50 K and 770 K SNP genotypes scored in 5,133 animals from 4 independent beef cattle populations (Cycle VII, Angus, Hereford and Simmental × Angus) with phenotypes for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake.

Results

A total of 5, 6, 11 and 10 significant QTL (defined as 1-Mb genome windows with Bonferroni-corrected P-value <0.05) were identified for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake, respectively. The identified QTL were population-specific and had little overlap across the 4 populations. The pleiotropic or closely linked QTL on BTA 7 at 23 Mb identified in the Angus population harbours a promising candidate gene ACSL6 (acyl-CoA synthetase long-chain family member 6), and was the largest effect QTL associated with dry matter intake and mid-test body weight explaining 10.39% and 14.25% of the additive genetic variance, respectively. Pleiotropic or closely linked QTL associated with average daily gain and mid-test body weight were detected on BTA 6 at 38 Mb and BTA 7 at 93 Mb confirming previous reports. No QTL for residual feed intake explained more than 2.5% of the additive genetic variance in any population. Marker-based estimates of heritability ranged from 0.21 to 0.49 for residual feed intake across the 4 populations.

Conclusions

This GWAS study, which is the largest performed for feed efficiency and its component traits in beef cattle to date, identified several large-effect QTL that cumulatively explained a significant percentage of additive genetic variance within each population. Differences in the QTL identified among the different populations may be due to differences in power to detect QTL, environmental variation, or differences in the genetic architecture of trait variation among breeds. These results enhance our understanding of the biology of growth, feed intake and utilisation in beef cattle.     

SNPs associated with body weight and backfat thickness in two pig breeds identified by a genome-wide association study

Growth and fat deposition are important economic traits due to the influence on production in pigs. In this study, a dataset of 1200 pigs with 345,570 SNPs genotyped by sequencing (GBS) was used to conduct a GWAS with single-marker regression method to identify SNPs associated with body weight and backfat thickness (BFT) and to search for candidate genes in Landrace and Yorkshire pigs. A total of 27 and 13 significant SNPs were associated with body weight and BFT, respectively. In the region of 149.85–149.89 Mb on SSC6, the SNP (SSC6: 149876737) for body weight and the SNP (SSC6: 149876507) for BFT were in the same locus region (a gap of 230 bp). Two SNPs were located in the DOCK7 gene, which is a protein-coding gene that plays an important role in pigmentation. Two SNPs located on SSC8: 54567459 and SSC11: 33043081 were found to overlap weight and BFT; however, no candidate gene was found in these regions. In addition, based on other significant SNPs, two positional candidate genes, NSRP1 and CADPS, were proposed to influence weight. In conclusion, this is the first study report using GBS data to identify the significant SNPs for weight and BFT. A total of four particularly interesting SNPs and one potential candidate genes (DOCK7) were found for these traits in domestic pigs. This study improves our knowledge to better understand the complex genetic architecture of weight and BFT, but further validation studies of these candidate loci and genes are recommended in pigs     

Analysis of growth patterns in purebred Kambing Katjang goat and its crosses with the German Fawn

The objective of this study was to investigate growth patterns of goats utilizing data from a crossbreeding program involving the exotic German Fawn (GF) and the indigenous Kambing Katjang (KK) goats. Growth curve models and growth curve parameters were compared and analyzed for different genotypes and litter types. A total of 20,393 weight–age data from 208 female goats belonging to various crossbreeding genotypes were individually fitted to four growth curve models (Brody, Bertalanffy, Gompertz and Logistic). The goodness of fit was highest in the Brody model in most cases. A comparison of R² among genotypes showed that they were highest for KK. There were no significant differences of genotypes for estimated mature weight in the Brody model. The estimated mature weights for KK were significantly lower (P < 0.05) than for GF × KK (F₁), backcrosses with 75% GF genes (BC) and F₁ × F₁ (F₂) in the other models. The correlations between estimated mature weights and the maturing rates were lowest for BC. The genotype significantly (P < 0.01) affected the age at the constant degree of maturity (67% and 90% of mature weight) in all models. The BC genotype was the youngest at maturity and KK the oldest. All models well expressed the growth pattern of the target animals when they were older than 2.5 years of age. The results from the present study showed that the growth pattern may be altered by crossbreeding of KK with the GF breed.     

Effect of Feeding Selenium-Fertilized Alfalfa Hay on Performance of Weaned Beef Calves

Selenium (Se) is an essential micronutrient in cattle, and Se-deficiency can affect morbidity and mortality. Calves may have greater Se requirements during periods of stress, such as during the transitional period between weaning and movement to a feedlot. Previously, we showed that feeding Se-fertilized forage increases whole-blood (WB) Se concentrations in mature beef cows. Our current objective was to test whether feeding Se-fertilized forage increases WB-Se concentrations and performance in weaned beef calves. Recently weaned beef calves (n = 60) were blocked by body weight, randomly assigned to 4 groups, and fed an alfalfa hay based diet for 7 wk, which was harvested from fields fertilized with sodium-selenate at a rate of 0, 22.5, 45.0, or 89.9 g Se/ha. Blood samples were collected weekly and analyzed for WB-Se concentrations. Body weight and health status of calves were monitored during the 7-wk feeding trial. Increasing application rates of Se fertilizer resulted in increased alfalfa hay Se content for that cutting of alfalfa (0.07, 0.95, 1.55, 3.26 mg Se/kg dry matter for Se application rates of 0, 22.5, 45.0, or 89.9 g Se/ha, respectively). Feeding Se-fertilized alfalfa hay during the 7-wk preconditioning period increased WB-Se concentrations (P _Linear<0.001) and body weights (P _Linear = 0.002) depending upon the Se-application rate. Based upon our results we suggest that soil-Se fertilization is a potential management tool to improve Se-status and performance in weaned calves in areas with low soil-Se concentrations.     

Identification of genetic loci associated with growth traits at weaning in yak through a genome-wide association study

A multilocus GWAS was performed to explore the genetic architecture of four growth traits in yak. In total, 354 female yaks for which measurements of body weight (BW), withers height (WH), body length (BL) and chest girth (CG) at weaning were available underwent genotyping with the Illumina BovineHD BeadChip (770K). After quality control, we retained 98 688 SNPs and 354 animals for GWAS analysis. We identified seven, 18, seven and nine SNPs (corresponding to seven, 17, seven and eight candidate genes) associated with BW, WH, BL and CG at weaning respectively. Interestingly, most of these candidate genes were reported to be involved in growth-related processes such as muscle formation, lipid deposition, feed efficiency, carcass composition and development of the central and peripheral nervous system. Our results offer novel insight into the molecular architecture underpinning yak growth traits. Further functional analyses are thus warranted to explore the molecular mechanisms whereby these genes affect these traits of interest.