BMC Genetics - Latest Articles

Efficiency of genomic selection using Bayesian multimarker models for traits selected to reflect a wide range of heritabilities and frequencies of detected quantitative traits loci in mice

Dagmar Kapell — 2012-05-31T00:00:00Z

Background: Genomic selection uses dense single nucleotide polymorphisms (SNP) markers to predictbreeding values, as compared to conventional evaluations which estimate polygenic effectsbased on phenotypic records and pedigree information. The objective of this study was tocompare polygenic, genomic and combined polygenic-genomic models, including mixturemodels (labelled according to the percentage of genotyped SNP markers considered to have asubstantial effect, ranging from 2.5 % to 100 %). The data consisted of phenotypes and SNPgenotypes (10,946 SNPs) of 2,188 mice. Various growth, behavioural and physiological traitswere selected for the analysis to reflect a wide range of heritabilities (0.10 to 0.74) andnumbers of detected quantitative traits loci (QTL) (1 to 20) affecting those traits. The analysisincluded estimation of variance components and cross-validation within and betweenfamilies. Results: Genomic selection showed a high predictive ability (PA) in comparison to traditionalpolygenic selection, especially for traits of moderate heritability and when cross-validationwas between families. This occurred although the proportion of genomic variance of traitsusing genomic models was 22 to 33 % smaller than using polygenic models. Using a 2.5 %mixture genomic model, the proportion of genomic variance was 79 % smaller relative to thepolygenic model. Although the proportion of variance explained by the markers was reducedfurther when a smaller number of SNPs was assumed to have a substantial effect on the trait,PA of genomic selection for most traits was little affected. These low mixture percentagesresulted in improved estimates of single SNP effects. Genomic models implemented for traitswith fewer QTLs showed even lower PA than the polygenic models. Conclusions: Genomic selection generally performed better than traditional polygenic selection, especiallyin the context of between family cross-validation. Reducing the number of markersconsidered to affect the trait did not significantly change PA for most traits, particularly in thecase of within family cross-validation, but increased the number of markers found to beassociated with QTLs. The underlying number of QTLs affecting the trait has an effect onPA, with a smaller number of QTLs resulting in lower PA using the genomic modelcompared to the polygenic model.

Genome-wide linkage analysis of QTL for growth and body composition employing the PorcineSNP60 BeadChip

Ana Isabel Fernández — 2012-05-20T00:00:00Z

Background: The traditional strategy to map QTL is to use linkage analysis employing a limited number ofmarkers. These analyses report wide QTL confidence intervals, making very difficult toidentify the gene and polymorphisms underlying the QTL effects. The arrival of genomewidepanels of SNPs makes available thousands of markers increasing the informationcontent and therefore the likelihood of detecting and fine mapping QTL regions. The aims ofthe current study are to confirm previous QTL regions for growth and body composition traitsin different generations of an Iberian x Landrace intercross (IBMAP) and especially identifynew ones with narrow confidence intervals by employing the PorcineSNP60 BeadChip inlinkage analyses. Results: Three generations (F3, Backcross 1 and Backcross 2) of the IBMAP and their related animalswere genotyped with PorcineSNP60 BeadChip. A total of 8,417 SNPs equidistantlydistributed across autosomes were selected after filtering by quality, position and frequencyto perform the QTL scan. The joint and separate analyses of the different IBMAP generationsallowed confirming QTL regions previously identified in chromosomes 4 and 6 as well asnew ones mainly for backfat thickness in chromosomes 4, 5, 11, 14 and 17 and shoulderweight in chromosomes 1, 2, 9 and 13; and many other to the chromosome-wide significationlevel. In addition, most of the detected QTLs displayed narrow confidence intervals, makingeasier the selection of positional candidate genes. Conclusions: The use of higher density of markers has allowed to confirm results obtained in previousQTL scans carried out with microsatellites. Moreover several new QTL regions have beennow identified in regions probably not covered by markers in previous scans, most of theseQTLs displayed narrow confidence intervals. Finally, prominent putative biological andpositional candidate genes underlying those QTL effects are listed based on recent porcinegenome annotation.

Genome-wide association study identified three major QTL for carcass weight including the PLAG1-CHCHD7 QTN for stature in Japanese Black cattle

Shota Nishimura — 2012-05-20T00:00:00Z

Background: Significant quantitative trait loci (QTL) for carcass weight were previously mapped onseveral chromosomes in Japanese Black half-sib families. Two QTL, CW-1 and CW-2, werenarrowed down to 1.1-Mb and 591-kb regions, respectively. Recent advances in genomictools allowed us to perform a genome-wide association study (GWAS) in cattle to detectassociations in a general population and estimate their effect size. Here, we performed aGWAS for carcass weight using 1156 Japanese Black steers. Results: Bonferroni-corrected genome-wide significant associations were detected in threechromosomal regions on bovine chromosomes (BTA) 6, 8, and 14. The associated singlenucleotide polymorphisms (SNP) on BTA 6 were in linkage disequilibrium with the SNPencoding NCAPG Ile442Met, which was previously identified as a candidate quantitativetrait nucleotide for CW-2. In contrast, the most highly associated SNP on BTA 14 waslocated 2.3-Mb centromeric from the previously identified CW-1 region. Linkagedisequilibrium mapping led to a revision of the CW-1 region within a 0.9-Mb interval aroundthe associated SNP, and targeted resequencing followed by association analysis highlightedthe quantitative trait nucleotide for bovine stature in the PLAG1-CHCHD7 intergenic region.The association on BTA 8 was accounted for by two SNP on the BovineSNP50 BeadChipand corresponded to CW-3, which was simultaneously detected by linkage analyses usinghalf-sib families. The allele substitution effects of CW-1, CW-2, and CW-3 were 28.4, 35.3,and 35.0 kg per allele, respectively. Conclusion: The GWAS revealed the genetic architecture underlying carcass weight variation in JapaneseBlack cattle in which three major QTL accounted for approximately one-third of the geneticvariance.

Genetic analysis of ancestry, admixture and selection in Bolivian and Totonac populations of the New World

W Scott Watkins — 2012-05-20T00:00:00Z

Background: Populations of the Americas were founded by early migrants from Asia, and some haveexperienced recent genetic admixture. To better characterize the native and non-nativeancestry components in populations from the Americas, we analyzed 815,377 autosomalSNPs, mitochondrial hypervariable segments I and II, and 36 Y-chromosome STRs from 24Mesoamerican Totonacs and 23 South American Bolivians.Results and conclusionsWe analyzed common genomic regions from native Bolivian and Totonac populations toidentify 324 highly predictive Native American ancestry informative markers (AIMs). As fewas 40-50 of these AIMs perform nearly as well as large panels of random genome-wide SNPsfor predicting and estimating Native American ancestry and admixture levels. These AIMshave greater New World vs. Old World specificity than previous AIMs sets. We identifyhighly-divergent New World SNPs that coincide with high-frequency haplotypes found atsimilar frequencies in all populations examined, including the HGDP Pima, Maya,Colombian, Karitiana, and Surui American populations. Some of these regions are potentialcandidates for positive selection. European admixture in the Bolivian sample isapproximately 12%, though individual estimates range from 0-48%. We estimate that theadmixture occurred ~360-384 years ago. Little evidence of European or African admixturewas found in Totonac individuals. Bolivians with pre-Columbian mtDNA and Ychromosomehaplogroups had 5-30% autosomal European ancestry, demonstrating thelimitations of Y-chromosome and mtDNA haplogroups and the need for autosomal ancestryinformative markers for assessing ancestry in admixed populations.

Genetic divergence and the genetic architecture of complex traits in chromosome substitution strains of mice

Sabrina Spiezio — 2012-05-18T00:00:00Z

Background: The genetic architecture of complex traits strongly influences the consequences of inheritedmutations, genetic engineering, environmental and genetic perturbations, and natural andartificial selection. But because most studies are under-powered, the picture of complex traitsis often incomplete. Chromosome substitution strains (CSSs) are a unique paradigm for thesegenome surveys because they enable statistically independent, powerful tests for thephenotypic effects of each chromosome on a uniform inbred genetic background. A previousCSS survey in mice and rats revealed many complex trait genes (QTLs), large phenotypiceffects, extensive epistasis, as well as systems properties such as strongly directionalphenotypic changes and genetically-determined limits on the range of phenotypic variation.However, the unusually close genetic relation between the CSS progenitor strains in thatstudy raised questions about the impact of genetic divergence: would greater divergencebetween progenitor strains, with the corresponding changes in gene regulation and proteinfunction, lead to significantly more distinctive phenotypic features, or alternatively wouldepistasis and systems constraints, which are pervasive in CSSs, limit the range of phenotypicvariation regardless of the extent of DNA sequence variation? Results: We analyzed results for an extensive survey of traits in two new panels of CSSs where thedonor strains were derived from inbred strains with more distant origins and discovered astrong similarity in genetic and systems properties among the three CSS panels, regardless ofdivergence time. Conclusion: Our results argue that DNA sequence differences between host and donor strains did notsubstantially affect the architecture of complex traits, and suggest instead that strong epistasisbuffered the phenotypic effects of genetic divergence, thereby constraining the range ofphenotypic variation.

Artificial neural networks modeling gene-environment interaction

Frauke Günther — 2012-05-14T00:00:00Z

Background: Gene-environment interactions play an important role in the etiological pathway of complexdiseases. An appropriate statistical method for handling a wide variety of complex situationsinvolving interactions between variables is still lacking, especially when continuous variables areinvolved. The aim of this paper is to explore the ability of neural networks to model differentstructures of gene-environment interactions. A simulation study is set up to compare neuralnetworks with standard logistic regression models. Eight different structures of gene-environmentinteractions are investigated. These structures are characterized by penetrance functions that arebased on sigmoid functions or on combinations of linear and non-linear effects of a continuousenvironmental factor and a genetic factor with main effect or with a masking effect only. Results: In our simulation study, neural networks are more successful in modeling gene-environmentinteractions than logistic regression models. This outperfomance is especially pronounced whenmodeling sigmoid penetrance functions, when distinguishing between linear and nonlinearcomponents, and when modeling masking effects of the genetic factor. Conclusion: Our study shows that neural networks are a promising approach for analyzing gene-environmentinteractions. Especially, if no prior knowledge of the correct nature of the relationship betweenco-variables and response variable is present, neural networks provide a valuable alternative toregression methods that are limited to the analysis of linearly separable data.

Mcm2 phosphorylation and the response to replicative stress

Brent Stead — 2012-05-07T00:00:00Z

Background: The replicative helicase in eukaryotic cells is comprised of minichromosome maintenance(Mcm) proteins 2 through 7 (Mcm2-7) and is a key target for regulation of cell proliferation.In addition, it is regulated in response to replicative stress. One of the protein kinases thattargets Mcm2-7 is the Dbf4-dependent kinase Cdc7 (DDK). In a previous study, we showedthat alanine mutations of the DDK phosphorylation sites at S164 and S170 in Saccharomycescerevisiae Mcm2 result in sensitivity to caffeine and methyl methanesulfonate (MMS)leading us to suggest that DDK phosphorylation of Mcm2 is required in response toreplicative stress. Results: We show here that a strain with the mcm2 allele lacking DDK phosphorylation sites(mcm2AA) is also sensitive to the ribonucleotide reductase inhibitor, hydroxyurea (HU) and tothe base analogue 5-fluorouracil (5-FU) but not the radiomimetic drug, phleomycin. Wescreened the budding yeast non-essential deletion collection for synthetic lethal interactionswith mcm2AA and isolated deletions that include genes involved in the control of genomeintegrity and oxidative stress. In addition, the spontaneous mutation rate, as measured bymutations in CAN1, was increased in the mcm2AA strain compared to wild type, whereas witha phosphomimetic allele (mcm2EE) the mutation rate was decreased. These results led to theidea that the mcm2AA strain is unable to respond properly to DNA damage. We examined thisby screening the deletion collection for suppressors of the caffeine sensitivity of mcm2AA.Deletions that decrease spontaneous DNA damage, increase homologous recombination orslow replication forks were isolated. Many of the suppressors of caffeine sensitivitysuppressed other phenotypes of mcm2AA including sensitivity to genotoxic drugs, theincreased frequency of cells with RPA foci and the increased mutation rate. Conclusions: Together these observations point to a role for DDK-mediated phosphorylation of Mcm2 inthe response to replicative stress, including some forms of DNA damage. We suggest thatphosphorylation of Mcm2 modulates Mcm2-7 activity resulting in the stabilization ofreplication forks in response to replicative stress.

Ascertaining gene flow patterns in livestock populations of developing countries: a case study in Burkina Faso goat

Amadou Traoré — 2012-05-07T00:00:00Z

Background: Introgression of Sahel livestock genes southwards in West Africa may be favoured by humanactivity and the increase of the duration of the dry seasons since the 1970's. The aim of thisstudy is to assess the gene flow patterns in Burkina Faso goat and to ascertain the most likelyfactors influencing geographic patterns of genetic variation in the Burkina Faso goatpopulation. Results: A total of 520 goat were sampled in 23 different locations of Burkina Faso and genotyped fora set of 19 microsatellites. Data deposited in the Dryad repository:http://dx.doi.org/10.5061/dryad.41h46j37. Although overall differentiation is poor (FST =0.067 +/- 0.003), the goat population of Burkina Faso is far from being homogeneous. Barrieranalysis pointed out the existence of: a) genetic discontinuities in the Central and SoutheastBurkina Faso; and b) genetic differences within the goat sampled in the Sahel or the Sudanareas of Burkina Faso. Principal component analysis and admixture proportion scores werecomputed for each population sampled and used to construct interpolation maps.Furthermore, Population Graph analysis revealed that the Sahel and the Sudan environmentalareas of Burkina Faso were connected through a significant number of extended edges, whichwould be consistent with the hypothesis of long-distance dispersal. Genetic variation ofBurkina Faso goat followed a geographic-related pattern. This pattern of variation is likely tobe related to the presence of vectors of African animal trypanosomosis. Partial Mantel testidentified the present Northern limit of trypanosome vectors as the most significant landscapeboundary influencing the genetic variability of Burkina Faso goat (p = 0.008). Thecontribution of Sahel goat genes to the goat populations in the Northern and Eastern parts ofthe Sudan-Sahel area of Burkina Faso was substantial. The presence of perennial streamsexplains the existence of trypanosome vectors. The South half of the Nakambe river(Southern Ouagadougou) and the Mouhoun river loop determined, respectively, the Easternand Northern limits for the expansion of Sahelian goat genes. Furthermore, results frompartial Mantel test suggest that the introgression of Sahelian goat genes into Djallonke goatusing human-influenced genetic corridors has a limited influence when compared to thebiological boundary defined by the northern limits for the distribution of the tsetse fly.However, the genetic differences found between the goat sampled in Bobo Dioulasso and theother populations located in the Sudan area of Burkina Faso may be explained by the broadgoat trade favoured by the main road of the country. Conclusions: The current analysis clearly suggests that genetic variation in Burkina Faso goat: a) follows aNorth to South clinal; and b) is affected by the distribution of the tsetse fly that imposes alimit to the Sahelian goat expansion due to their trypanosusceptibility. Here we show howextensive surveys on livestock populations can be useful to indirectly assess theconsequences of climate change and human action in developing countries.

Gene diversity, agroecological structure and introgression patterns among village chicken populations across North, West and Central Africa

Grégoire Leroy — 2012-05-07T00:00:00Z

Background: Chickens represent an important animal genetic resource for improving farmers' income inAfrica. The present study provides a comparative analysis of the genetic diversity of villagechickens across a subset of African countries. Four hundred seventy-two chickens weresampled in 23 administrative provinces across Cameroon, Benin, Ghana, Cote d'Ivoire, andMorocco. Geographical coordinates were recorded to analyze the relationships betweengeographic distribution and genetic diversity. Molecular characterization was performed witha set of 22 microsatellite markers. Five commercial lines, broilers and layers, were alsogenotyped to investigate potential gene flow. A genetic diversity analysis was conducted bothwithin and between populations. Results: High heterozygosity levels, ranging from 0.51 to 0.67, were reported for all local populations,corresponding to the values usually found in scavenging populations worldwide. Allelicrichness varied from 2.04 for a commercial line to 4.84 for one population from Coted'Ivoire. Evidence of gene flow between commercial and local populations was observed inMorocco and in Cameroon, which could be related to long-term improvement programs withthe distribution of crossbred chicks. The impact of such introgressions seemed rather limited,probably because of poor adaptation of exotic birds to village conditions, and because of theconsumers' preference for local chickens. No such gene flow was observed in Benin, Ghana,and Cote d'Ivoire, where improvement programs are also less developed. The clusteringapproach revealed an interesting similarity between local populations found in regionssharing high levels of precipitation, from Cameroon to Cote d'Ivoire. Restricting the study toBenin, Ghana, and Cote d'Ivoire, did not result in a typical breed structure but a south-west tonorth-east gradient was observed. Three genetically differentiated areas (P < 0.01) wereidentified, matching with Major Farming Systems (namely Tree Crop, Cereal-Root Crop, andRoot Crop) described by the FAO. Conclusions: Local chickens form a highly variable gene pool constituting a valuable resource for humanpopulations. Climatic conditions, farming systems, and cultural practices may influence thegenetic diversity of village chickens in Africa. A higher density of markers would be neededto identify more precisely the relative importance of these factors.

Genetic characterization of Plectorhinchus mediterraneus yields important clues about genome organization and evolution of multigene families

Manuel Merlo — 2012-04-30T00:00:00Z

Background: Molecular and cytogenetic markers are of great use for to fish characterization, identification,phylogenetics and evolution. Multigene families have proven to be good markers for a betterunderstanding of the variability, organization and evolution of fish species. Three differenttandemly-repeated gene families (45S rDNA, 5S rDNA and U2 snDNA) have been studied inPlectorhinchus mediterraneus (Teleostei: Haemulidae), at both molecular and cytogeneticlevel, to elucidate the taxonomy and evolution of these multigene families, as well as forcomparative purposes with other species of the family. Results: Four different types of 5S rDNA were obtained; two of them showed a high homology withthat of Raja asterias, and the putative implication of a horizontal transfer event and itsconsequences for the organization and evolution of the 5S rDNA have been discussed. Theother two types do not resemble any other species, but in one of them a putative tRNAderivedSINE was observed for the first time, which could have implications in the evolutionof the 5S rDNA. The ITS-1 sequence was more related to a species of another different genusthan to that of the same genus, therefore a revision of the Hamulidae family systematic hasbeen proposed. In the analysis of the U2 snDNA, we were able to corroborate that U2 snDNAand U5 snDNA were linked in the same tandem array, and this has interest for tracingevolutionary lines. The karyotype of the species was composed of 2n = 48 acrocentricchromosomes, and each of the three multigene families were located in different chromosomepairs, thus providing three different chromosomal markers. Conclusions: Novel data can be extracted from the results: a putative event of horizontal transfer, apossible tRNA-derived SINE linked to one of the four 5S rDNA types characterized, and alinkage between U2 and U5 snDNA. In addition, a revision of the taxonomy of theHaemulidae family has been suggested, and three cytogenetic markers have been obtained.Some of these results have not been described before in any other fish species. New cluesabout the genome organization and evolution of the multigene families are offered in thisstudy.