Selection signatures for high-altitude adaptation in ruminants.

High-altitude areas are important socio-economical habitats with ruminants serving as a major source of food and commodities for humans. Living at high altitude, however, is extremely challenging, predominantly due to the exposure to hypoxic conditions, but also because of cold temperatures and limited feed for livestock. To survive in high-altitude environments over the long term, ruminants have evolved adaptation strategies, e.g. physiological and morphological modifications, which allow them to cope with these harsh conditions. Identification of such selection signatures in ruminants may contribute to more informed breeding decisions, and thus improved productivity. Moreover, studying the genetic background of altitude adaptation in ruminants provides insights into a common molecular basis across species and thus a better understanding of the physiological basis of this adaptation. In this paper, we review the major effects of high altitude on the mammalian body and highlight some of the most important short-term (coping) and genetically evolved (adaptation) physiological modifications. We then discuss the genetic architecture of altitude adaptation and target genes that show evidence of being under selection based on recent studies in various species, with a focus on ruminants. The yak is presented as an interesting native species that has adapted to the high-altitude regions of Tibet. Finally, we conclude with implications and challenges of selection signature studies on altitude adaptation in general. We found that the number of studies on genetic mechanisms that enable altitude adaptation in ruminants is growing, with a strong focus on identifying selection signatures, and hypothesise that the investigation of genetic data from multiple species and regions will contribute greatly to the understanding of the genetic basis of altitude adaptation.

Accuracy of genotype imputation in Labrador Retrievers.

The dog is a valuable model species for the genetic analysis of complex traits, and the use of genotype imputation in dogs will be an important tool for future studies. It is of particular interest to analyse the effect of factors like single nucleotide polymorphism (SNP) density of genotyping arrays and relatedness between dogs on imputation accuracy due to the acknowledged genetic and pedigree structure of dog breeds. In this study, we simulated different genotyping strategies based on data from 1179 Labrador Retriever dogs. The study involved 5826 SNPs on chromosome 1 representing the high density (HighD) array; the low-density (LowD) array was simulated by masking different proportions of SNPs on the HighD array. The correlations between true and imputed genotypes for a realistic masking level of 87.5% ranged from 0.92 to 0.97, depending on the scenario used. A correlation of 0.92 was found for a likely scenario (10% of dogs genotyped using HighD, 87.5% of HighD SNPs masked in the LowD array), which indicates that genotype imputation in Labrador Retrievers can be a valuable tool to reduce experimental costs while increasing sample size. Furthermore, we show that genotype imputation can be performed successfully even without pedigree information and with low relatedness between dogs in the reference and validation sets. Based on these results, the impact of genotype imputation was evaluated in a genome-wide association analysis and genomic prediction in Labrador Retrievers.

Use of high-density SNP data to identify patterns of diversity and signatures of selection in broiler chickens.

The development of broiler chickens over the last 70 years has been accompanied by large phenotypic changes, so that the resulting genomic signatures of selection should be detectable by current statistical techniques with sufficiently dense genetic markers. Using two approaches, this study analysed high-density SNP data from a broiler chicken line to detect low-diversity genomic regions characteristic of past selection. Seven regions with zero diversity were identified across the genome. Most of these were very small and did not contain many genes. In addition, fifteen regions were identified with diversity increasing asymptotically from a low level. These regions were larger and thus generally included more genes. Several candidate genes for broiler traits were found within these 'regression regions', including IGF1, GPD2 and MTNR1AI. The results suggest that the identification of zero-diversity regions is too restrictive for characterizing regions under selection, but that regions showing patterns of diversity along the chromosome that are consistent with selective sweeps contain a number of genes that are functional candidates for involvement in broiler development. Many regions identified in this study overlap or are close to regions identified in layer chicken populations, possibly due to their shared precommercialization history or to shared selection pressures between broilers and layers.

Polymorphisms in twelve candidate genes are associated with growth, muscle lipid profile and meat quality traits in eleven European cattle breeds.

Current customers' demands focus on the nutritional and sensory quality of cattle meat. Candidate gene approach allows identification of genetic polymorphisms that have a measurable effect on traits of interest. The aim of this work is to identify new molecular markers for beef production through an association study using 27 candidate genes and 314 purebred bulls from 11 European cattle breeds. Twelve genes were found associated with different lipid and meat quality traits, and among these stand out the considerable effect of CAST on fatness score, CGGBP1 on growth traits, HSPB1 on the percentage of lauric acid (12:0) and phospholipid docosahexaenoic acid (DHA 22:6 n - 3), RORA on the ratio of light absorption (K) to light scattering (S) (K/S), and TNFA on lightness (L*). Most of these traits are related to post-mortem muscle biochemical changes, which are key factors controlling meat quality and consumers' acceptance. Also, the variations produced on muscle fatty acid profiles, such as those of AANAT, CRH, CSN3, HSPB1, and TNFA, give insights into the genetic networks controlling these complex traits and the possibility of future improvement of meat nutritional quality.

Assessing the impact of genomic selection against hip dysplasia in the Labrador Retriever dog.

Many purebred dogs exhibit a higher prevalence of inherited diseases compared with non-purebred dogs. One of the most popular breeds in the UK is the Labrador Retriever, which has a high prevalence of hip dysplasia resulting in high costs for surgical operations and impaired animal welfare. Considering the many complications of highly managed populations, mainly due to breeder's conventions and the resulting population structure, is of great importance for the proper development of a strategy against the disease. In this study, we have compared the utilities and performances of both genomic and phenotypic selection against hip dysplasia in a simulated population with the characteristics of the British Veterinary Association and Kennel Club (BV /KC) hip dysplasia scheme. The results confirm the potential benefits of genomic selection by showing a moderate increase of 1.15-fold (assuming a realistic accuracy of r(2) = 0.5) in response to selection due to the higher accuracy (between 0.96- and 1.32-fold, considering 0.35 ≤ r(2) ≤ 0.7) and more than a threefold increase when all the offspring in each litter are tested (between 3.25- and 4.55-fold, again considering 0.35 ≤ r(2) ≤ 0.7).

Investigation of the genetic architecture of a bone carcass weight QTL on BTA6.

A previous analysis of an F(2) /Backcross Charolais × Holstein cross population identified the presence of a highly significant QTL on chromosome 6 (BTA6) affecting the proportion of bone in the carcass. Two closely linked QTL affected birth weight (BW) and body length at birth (BBL). In this report, the marker density around the QTL on BTA6 was increased, adding four additional microsatellite markers across the chromosome and 46 SNPs within the target QTL confidence interval. Of the SNPs, 26 were in positional candidate genes and the remaining 20 provided an even distribution of markers in the target QTL region. As a bone-related trait, the sum of the bone weight for all the left fore- and hindquarter joints of the carcass was analysed. We also studied the BW and BBL. Analyses of the data substantially reduced the QTL confidence interval. No strong evidence was found that the QTL for the three traits studied are different, and we conclude that the results are consistent with a single pleiotropic QTL influencing the three traits, with the largest effects on the proportion of bone in the carcass. The analyses also suggest that none of the SNPs tested is the sole causative variant of the QTL effects. Specifically, the SNP in the NCAPG gene previously reported as a causal mutation for foetal growth and carcass traits in other cattle populations was excluded as the causal mutation for the QTL reported here. Polymorphisms located in other previously identified candidate genes including SPP1, ABCG2, IBSP, MEPE and PPARGC1A were also excluded. The results suggest that SNP51_BTA-119876 is the polymorphism in strongest linkage disequilibrium with the causal mutation(s). Further research is required to identify the causal variant(s) associated with this bone-related QTL.

Identification of polymorphisms in the malic enzyme 1, NADP(+)-dependent, cytosolic and nuclear receptor subfamily 0, group B, member 2 genes and their associations with meat and carcass quality traits in commercial Angus cattle.

Genes involved in the physiological control of energy and triglyceride synthesis, such as malic enzyme 1, NADP(+)-dependent, cytosolic (ME1) and nuclear receptor subfamily 0, group B, member 2 (NR0B2), are key candidates that may have effects on meat and carcass quality traits. These genes were sequenced in Aberdeen Angus beef cattle, and the possibility of associations between SNPs and economically important carcass and meat quality traits was tested. Six novel SNPs, five in ME1 and one in NR0B2, were identified. A SNP in exon eight of ME1 resulted in a non-synonymous amino acid change from valine to isoleucine. Phenotypic data were recorded on 536 commercial Aberdeen Angus-cross beef cattle, which comprised 28 carcass quality, tenderness and sensory traits. The majority of the SNPs were associated with at least one of these traits, including an association between the NR0B2 SNP and fat class, and associations between at least one of the ME1 SNPs and eye muscle area, sirloin weight before maturation, sirloin steak tail length, and juiciness.

Characterization of the genetic diversity, structure and admixture of British chicken breeds.

The characterization of livestock genetic diversity can inform breed conservation initiatives. The genetic diversity and genetic structure were assessed in 685 individual genotypes sampled from 24 British chicken breeds. A total of 239 alleles were found across 30 microsatellite loci with a mean number of 7.97 alleles per locus. The breeds were highly differentiated, with an average F(ST) of 0.25, similar to that of European chicken breeds. The genetic diversity in British chicken breeds was comparable to that found in European chicken breeds, with an average number of alleles per locus of 3.59, ranging from 2.00 in Spanish to 4.40 in Maran, and an average expected heterozygosity of 0.49, ranging from 0.20 in Spanish to 0.62 in Araucana. However, the majority of breeds were not in Hardy-Weinberg Equilibrium, as indicated by heterozygote deficiency in the majority of breeds (average F(IS) of 0.20), with an average observed heterozygote frequency of 0.39, ranging from 0.15 in Spanish to 0.49 in Cochin. Individual-based clustering analyses revealed that most individuals clustered to breed origin. However, genetic subdivisions occurred in several breeds, and this was predominantly associated with flock supplier and occasionally by morphological type. The deficit of heterozygotes was likely owing to a Wahlund effect caused by sampling from different flocks, implying structure within breeds. It is proposed that gene flow amongst flocks within breeds should be enhanced to maintain the current levels of genetic diversity. Additionally, certain breeds had low levels of both genetic diversity and uniqueness. Consideration is required for the conservation and preservation of these potentially vulnerable breeds.

A cattle graph genome incorporating global breed diversity.

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds, especially those from Africa for which genomic resources are particularly limited, despite their disproportionate importance to the continent's economies. To mitigate this issue, we have generated assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into a graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1 Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research.

An empirical assessment of individual-based population genetic statistical techniques: application to British pig breeds.

Recently developed Bayesian genotypic clustering methods for analysing genetic data offer a powerful tool to evaluate the genetic structure of domestic farm animal breeds. The unit of study with these approaches is the individual instead of the population. We aimed to empirically evaluate various individual-based population genetic statistical methods for characterization of genetic diversity and structure of livestock breeds. Eighteen British pig populations, comprising 819 individuals, were genotyped at 46 microsatellite markers. Three Bayesian genotypic clustering approaches, principle component analysis (PCA) and phylogenetic reconstruction were applied to individual multilocus genotypes to infer the genetic structure and diversity of the British pig breeds. Comparisons of the three Bayesian genotypic clustering methods (STRUCTURE, BAPS and STRUCTURAMA) revealed some broad similarities but also some notable differences. Overall, the methods agreed that majority of the British pig breeds are independent genetic units with little evidence of admixture. The three Bayesian genotypic clustering methods provided complementary, biologically credible clustering solutions but at different levels of resolution. BAPS detected finer genetic differentiation and in some cases, populations within breeds. Consequently, it estimated a greater number of underlying genetic populations (K, in the notation of Bayesian clustering methods). Two of the Bayesian methods (STRUCTURE and BAPS) and phylogenetic reconstruction provided similar success in assignment of individuals, supporting the use of these methods for breed assignment.

Assessment of selection mapping near the myostatin gene (GDF-8) in cattle.

Domestic species provide a unique opportunity to examine the effects of selection on the genome. The myostatin gene (GDF-8) has been under strong selection in a number of cattle breeds because of its influence on muscle conformation and association with the 'double-muscling' phenotype. This study examined genetic diversity near this gene in a set of breeds including some nearly fixed for the allele associated with double-muscling (MH), some where the allele is segregating at intermediate frequency and some where the allele is absent. A set of microsatellites and SNPs were used to examine patterns of diversity at the centromeric end of bovine chromosome 2, the region where GDF-8 is located, using various statistical methods. The putative position of a selected gene was moved across the genomic region to determine, by regression, a best position of reduced heterozygosity. Additional analyses examined extended homozygous regions and linkage disequilibrium patterns. While the SNP data was not found to be very informative for selection mapping in this dataset, analyses of the microsatellite data provided evidence of selection on GDF-8 in several breeds. These results suggested that, of the breeds examined, the allele was most recently introduced into the South Devon. Limitations to the selection-mapping approach were highlighted from the analysis of the SNP data and the situation where the MH allele was at intermediate frequency.

Associations between the 11-bp deletion in the myostatin gene and carcass quality in Angus-sired cattle.

An 11-bp deletion in the bovine myostatin (MSTN) gene was identified as the causative mutation for the double-muscling phenotype in Belgian Blue and Asturiana cattle. More recently, this mutation was also identified in the South Devon breed of cattle, in which it has been found to be associated with a general increase in muscle mass. The present study found that the mutant allele was also segregating in a commercial population of Scottish Aberdeen Angus beef cattle. The mutation was found at a low frequency (0.04) with no animals homozygous for the mutation in the sample population (536 animals). The effects of this mutation on various carcass traits of economic interest were then tested. We found that the mutation significantly increased carcass weight, sirloin weight, hindquarter weight, muscle conformation score and eye muscle area, but had no effect on the fat traits.

The effects of a mutation in the myostatin gene on meat and carcass quality.

This study examined the effects of a mutation that inactivates the myostatin gene on calving, growth, carcass and meat quality traits in South Devon cattle. This breed carries at intermediate frequency an 11-bp deletion (MH) in the myostatin gene, known to be associated with the double-muscling phenotype, thus allowing a comparison of three genotype classes. The MH allele was associated with increased calving difficulty, carcass weight, muscle conformation and ratio of polyunsaturated to saturated fatty acids, as well as with reduced growth rate, carcass and meat fatness, and desirable flavour. However, the nature of the genetic effects differed between traits: in some cases the heterozygote MH carriers were more similar to the non-carriers than to homozygote carriers and in some cases, intermediate between the two homozygotes. The direction of these genetic effects has implications for the management of this genetic variation in the South Devon and other breeds.

Detection of quantitative trait loci for meat quality traits in cattle.

A whole-genome scan was carried out to detect quantitative trait loci (QTL) affecting sensory, organoleptic, physical and chemical properties of meat. The study used phenotypic data from 235 second-generation cross-bred bull calves of a Charolais x Holstein experimental population. Loin muscle samples were evaluated for yield force, intramuscular fat and nitrogen contents, myofibrillar fragmentation index, haem pigment concentration, moisture content and pH at 24 h postmortem. A sensory assessment was performed on grilled loin and roasted silverside joints by trained panellists. A linear regression analysis based on 165 markers revealed 35 QTL at the 5% chromosome-wide significance level (20 for sensory traits and 15 for physical and chemical traits), five of which were highly significant (F-value: > or =9). The most significant QTL was located on chromosome 6 (with the best likely position at 39 cM) and affected haem pigment concentration. The Holstein allele for this QTL was associated with an increase of 0.53 SD in the haem scores. A QTL for pH(24h) was identified on chromosome 14 (at 40 cM) and a QTL for moisture content was identified on chromosome 22 (at 21 cM). Two highly significant QTL were identified for sensory panel-assessed traits: beef odour intensity (grilled sample) on chromosome 10 (at 119 cM), and juiciness (roast sample) on chromosome 16 (at 70 cM). The proportion of phenotypic variance explained by the significant QTL ranged from 3.6% (for nitrogen content on chromosome 10) to 9.5% (for juiciness, roast sample on chromosome 16).

Inferring frequency dependent selection from the molecular evolution of a rapidly evolving virus: a theoretical investigation.

Hypotheses have been put forward suggesting that immune selection generates much of the intra-patient genetic diversity of rapidly evolving viruses. A Monte Carlo simulation is presented which models sequence evolution in an HIV-like virus under selection from the immune system. Measurements of evolutionary change are then made from the resulting sequences, generating predicted outcomes for each scenario. Frequency dependent immune selection is shown by two statistical measurements to have a significant effect on viral sequence evolution. The use of drawing inferences about underlying evolutionary processes from samples of viral diversity in infected individuals is discussed.

Course of gentamicin nephrotoxicity.

Metabolic balance and morphologic studies were performed on rats receiving gentamicin 100 mg/kg/day for a period of 8--10 days and during the recovery period. Daily urine flow rate increased with the administration of gentamiccin and remained elevated up to 20 days following the discontinuation of gentamicin, although BUN and plasma creatinine were virtually normal 10 days after the discontinuation of gentamicin. During the development of renal failure means daily electrolyte excretion remained normal. During the recovery period, however, sodium and potassium excretion exceeded control values while chloride and net acid excretion remained normal. Proteinuria developed during the administration of gentamicin and returned to normal 6--10 days after the discontinuation of gentamicin. Ten days of netilmicin administration (150 mg/kg/day) resulted in only mild tubular degeneration and no azotemia.

Population biology, evolution, and immunology of vaccination and vaccination programs.

The purpose of prophylactic vaccination is to reduce morbidity and mortality in a population. Many questions related to the design of vaccines and vaccination programs require a population standpoint for their sharp formulation and laboratory and field studies to understand their immunologic background. Practical suggestions of the workshop included increased studies of age-specific immunity, better immunoepidemiologic surveillance, better design of efficacy studies, and more systematic sampling of parasite strains to study the evolutionary pressure exerted by vaccines. Theoretical immunology has much to contribute. One of the realizations of the workshop was the value of a strong interdisciplinary approach in vaccine development, utilizing relevant contributions from immunology, population biology, mathematical modeling, epidemiology, molecular biology, and virology.

Association of bovine meat quality traits with genes included in the PPARG and PPARGC1A networks.

Understanding which are the genetic variants underlying the nutritional and sensory properties of beef, enables improvement in meat quality. The aim of this study is to identify new molecular markers for meat quality through an association study using candidate genes included in the PPARG and PPARGC1A networks given their master role in coordinating metabolic adaptation in fat tissue, muscle and liver. Amongst the novel associations found in this study, selection of the positive marker variants of genes such as BCL3, LPL, PPARG, SCAP, and SCD will improve meat organoleptic characteristics and health by balancing the n-6 to n-3 fatty acid ratio in meat. Also previous results on GDF8 and DGAT1 were validated, and the novel ATF4, HNF4A and PPARGC1A associations, although slightly under the significance threshold, are consistent with their physiological roles. These data contribute insights into the complex gene-networks underlying economically important traits.

Consistency statistics and genetic parameters for taste panel assessed meat quality traits and their relationship with carcass quality traits in a commercial population of Angus-sired beef cattle.

Sensory traits, such as juiciness and tenderness, are known to be important to the consumer and thus will influence their consumption of meat, specifically beef. These traits are difficult to measure and often require the use of taste panels to assess the complex parameters involved in the eating experience. Such panels are potentially a large source of measurement error, which may reduce the effectiveness of breeding programmes based on the data they generate. The aim of this study was to assess the quality of such taste panel-derived sensory traits as well as calculating genetic parameters and residual correlations for these traits along with a further set of traditional carcass quality traits. The study examined a sample of 443 Aberdeen Angus-cross animals collected from 14 breeder-finisher farms throughout Scotland. To assess the quality of the taste panel measurements, three consistency statistics were calculated: (i) panel-member consistency, i.e. the extent to which an individual panel member varied in their scoring for a given trait over the period of the experiment; (ii) repeatability, i.e. the consistency with which an individual panel member was able to score a trait on repeated samples from the same animal; and (iii) reproducibility, i.e. the extent to which taste panel members agreed with each other when scoring a trait. These consistency statistics were moderately high, particularly for panel-member consistency and reproducibility, with values ranging from 0.48 to 0.81 and 0.43 to 0.73 respectively. Estimated heritabilities were low for most of the sensory taste-panel-evaluated traits where the maximum value was 0.16 for overall liking. Residual correlations were high between many of the closely related sensory traits, although few significant correlations were found between the carcass quality data and meat quality traits.