| 1. |
- Cortés, Andrés J., et al.
(författare)
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Molecular ecology and selection in the drought-related Asr gene polymorphisms in wild and cultivated common bean (Phaseolus vulgaris L.)
- 2012
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 13, s. 58-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The abscisic acid (ABA) pathway plays an important role in the plants' reaction to drought stress and ABA-stress response (Asr) genes are important in controlling this process. In this sense, we accessed nucleotide diversity at two candidate genes for drought tolerance (Asr1 and Asr2), involved in an ABA signaling pathway, in the reference collection of cultivated common bean (Phaseolus vulgaris L.) and a core collection of wild common bean accessions. Results: Our wild population samples covered a range of mesic (semi-arid) to very dry (desert) habitats, while our cultivated samples presented a wide spectrum of drought tolerance. Both genes showed very different patterns of nucleotide variation. Asr1 exhibited very low nucleotide diversity relative to the neutral reference loci that were previously surveyed in these populations. This suggests that strong purifying selection has been acting on this gene. In contrast, Asr2 exhibited higher levels of nucleotide diversity, which is indicative of adaptive selection. These patterns were more notable in wild beans than in cultivated common beans indicting that natural selection has played a role over long time periods compared to farmer selection since domestication. Conclusions: Together these results suggested the importance of Asr1 in the context of drought tolerance, and constitute the first steps towards an association study between genetic polymorphism of this gene family and variation in drought tolerance traits. Furthermore, one of our major successes was to find that wild common bean is a reservoir of genetic variation and selection signatures at Asr genes, which may be useful for breeding drought tolerance in cultivated common bean.
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| 2. |
- Rönnegård, Lars, et al.
(författare)
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Modelling dominance in a flexible intercross analysis
- 2009
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: We have extended FIA to include QTL dominance effects. The power of FIA was superior, or similar, to standard regression methods for QTL effects with dominance. The difference in power for FIA with or without dominance is expected to be small as long as the QTL effects are not overdominant. We suggest that FIA with only additive effects should be the standard model to be used, especially since it is more computationally efficient.
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| 3. |
- Cohen, JC, et al.
(författare)
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The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse
- 2004
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. Results: Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. Conclusions: In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.
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| 4. |
- Hellberg, Åsa, et al.
(författare)
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Two previously proposed P-1/P-2-differentiating and nine novel polymorphisms at the A4GALT (P-k) locus do not correlate with the presence of the P1 blood group antigen
- 2005
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 6:49
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Tidskriftsartikel (refereegranskat)abstract
- Background: The molecular genetics of the P blood group system and the absence of P1 antigen in the p phenotype are still enigmatic. One theory proposes that the same gene encodes for both the P1 and P-k glycosyltransferases, but no polymorphisms in the coding region of the P-k gene explain the P-1/P-2 phenotypes. We investigated the potential regulatory regions up- and downstream of the A4GALT (P-k) gene exons. Results: P-1 (n = 18) and P-2 (n = 9) samples from donors of mainly Swedish descent were analysed by direct sequencing of PCR-amplified 5'- and 3'-fragments surrounding the P-k coding region. Seventy-eight P-1 and P-2 samples were investigated with PCR using allele-specific primers (ASP) for two polymorphisms previously proposed as P-2-related genetic markers(- 551_-550insC, -160A>G). Haplotype analysis of single nucleotide polymorphisms was also performed with PCR-ASP. In similar to 1.5 kbp of the 3'-untranslated region one new insertion and four new substitutions compared to a GenBank sequence (AL049757) were found. In addition to the polymorphisms at positions - 550 and - 160, one insertion, two deletions and one substitution were found in similar to 1.0 kbp of the 5'-upstream region. All 20 P-2 samples investigated with PCR-ASP were homozygous for -550insC. However, so were 18 of the 58 P-1 samples investigated. Both the 20 P-2 and the 18 P-1 samples were also homozygous for -160G. Conclusion: The proposed P-2-specific polymorphisms, -551_-550insC and -160G, found in P-2 samples in a Japanese study were found here in homozygous form in both P-1 and P-2 donors. Since P-2 is the null allele in the P blood group system it is difficult to envision how these mutations would cause the P-2 phenotype. None of the novel polymorphisms reported in this study correlated with P-1/P-2 status and the P1/p mystery remains unsolved.
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| 5. |
- Hosseini Maaf, Bahram, et al.
(författare)
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ABO exon and intron analysis in individuals with the A(weak)B phenotype reveals a novel O-1v-A(2) hybrid allele that causes four missense mutations in the A transferase
- 2003
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Since the cloning in 1990 of cDNA corresponding to mRNA transcribed at the blood-group ABO locus, polymorphisms due to ethnic and/or phenotypic variations have been reported. Some subgroups have been explained at the molecular level, but unresolved samples are frequently encountered in the reference laboratory. Results: ABO blood grouping discrepancies were investigated serologically and by ABO genotyping [duplex polymerase-chain-reaction (PCR)-restriction-fragment-length-polymorphism (RFLP) and PCR-allele-specific-primer (ASP) across intron 6] and DNA sequencing of the ABO gene and its proposed regulatory elements. Blood samples from five individuals living in Portugal, Switzerland, Sweden and the USA were analysed. These individuals were confirmed to be of Black ethnic origin and had the unusual A(weak)B phenotype but appeared to have the A(2)B genotype without previously reported mutations associated with weak A or B expression. Sequencing of this A allele (having 467C>T and 1061delC associated with the common A(2) [A201] allele) revealed three mutations regularly encountered in the O-1v [O02] allele: 106C>T (Val36Phe), 188G>A (Arg63His), 220C>T (Pro74Ser) in exons 3, 4 and 5, respectively. The additional presence of 46G>A (Ala16Thr) was noted, whilst 189C>T that normally accompanies 188G>A in O-1v was missing, as were all O-1v-related mutations in exons 6 and 7 (261delG, 297A>G, 646T>A, 681G>A, 771C>T and 829G>A). On screening other samples, 46G>A was absent, but two new O alleles were found, a Jordanian O-1 and an African O1v allele having 188G>A but lacking 189C>T. Sequencing of introns 2, 3, 4 and 5 in common alleles (A(1)[A101], A(2), B [B101], O-1, O-1v and O-2 [O03]) revealed 7, 12, 17 and 8 polymorphic positions, respectively, suggesting that alleles could be defined by intronic sequences. These polymorphic sites allowed definition of a breakpoint in intron 5 where the O-1v-related sequence was fused with A(2) to form the new hybrid. Intron 6 has previously been sequenced. Four new mutations were detected in the hybrid allele and these were subsequently also found in intron 6 of A(2) alleles in other Black African samples. Conclusions: A novel O-1v-A(2) hybrid was defined by ABO exon/intron analysis in five unrelated individuals of African descent with the A(weak)B blood group phenotype.
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| 6. |
- Andersen, Oivind, et al.
(författare)
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Polymorphism, selection and tandem duplication of transferrin genes in Atlantic cod (Gadus morhua) - Conserved synteny between fish monolobal and tetrapod bilobal transferrin loci.
- 2011
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Ingår i: BMC genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The two homologous iron-binding lobes of transferrins are thought to have evolved by gene duplication of an ancestral monolobal form, but any conserved synteny between bilobal and monolobal transferrin loci remains unexplored. The important role played by transferrin in the resistance to invading pathogens makes this polymorphic gene a highly valuable candidate for studying adaptive divergence among local populations. RESULTS: The Atlantic cod genome was shown to harbour two tandem duplicated serum transferrin genes (Tf1, Tf2), a melanotransferrin gene (MTf), and a monolobal transferrin gene (Omp) expressed in the otoliths. Fish, chicken and mammals showed highly conserved syntenic regions in which monolobal and bilobal transferrins reside, but contrasting with tetrapods, the fish transferrin genes are positioned on three different linkage groups. Sequence alignment of cod Tf1 cDNAs from Northeast (NE) and Northwest (NW) Atlantic populations revealed 22 single nucleotide polymorphisms (SNP) causing the replacement of 16 amino acids, including eight surface residues revealed by the modelled 3D-structures, which might influence the binding of pathogens for removal of iron. SNP analysis of a total of 375 individuals from 14 trans-Atlantic populations showed that the Tf1-NE variant was almost fixed in the Baltic cod and predominated in the other NE Atlantic populations, whereas the NW Atlantic populations were more heterozygous and showed high frequencies of the Tf-NW SNP alleles. CONCLUSIONS: The highly conserved synteny between fish and tetrapod transferrin loci infers that the fusion of tandem duplicated Omp-like genes gave rise to the modern transferrins. The multiple nonsynonymous substitutions in cod Tf1 with putative structural effects, together with highly divergent allele frequencies among different cod populations, strongly suggest evidence for positive selection and local adaptation in trans-Atlantic cod populations.
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| 7. |
- Bains, Ripudaman K., et al.
(författare)
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Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa
- 2013
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 14, s. 34-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago. Results: We estimate that similar to 43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as similar to 76,400 years and CYP3A5*6 as similar to 218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann's Rho= -0.465, p=0.004] and 50,000 years ago [Spearmann's Rho= -0.379, p=0.02]. Conclusions: Significant intra-African diversity at the CYP3A5 gene is likely to contribute to multiple pharmacogenetic profiles across the continent. Significant correlations between CYP3A5 expression phenotypes and aridity data are consistent with a hypothesis that the enzyme is important in salt-retention adaptation.
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| 8. |
- Berlin, Sofia, et al.
(författare)
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A multilocus assay reveals high nucleotide diversity and limited differentiation among Scandinavian willow grouse (Lagopus lagopus)
- 2008
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 9, s. 89-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is so far very little data on autosomal nucleotide diversity in birds, except for data from the domesticated chicken and some passerines species. Estimates of nucleotide diversity reported so far in birds have been high (similar to 10(-3)) and a likely explanation for this is the generally higher effective population sizes compared to mammals. In this study, the level of nucleotide diversity has been examined in the willow grouse, a non-domesticated bird species from the order Galliformes, which also holds the chicken. The willow grouse (Lagopus lagopus) has an almost circumpolar distribution but is absent from Greenland and the north Atlantic islands. It primarily inhabits tundra, forest edge habitats and sub-alpine vegetation. Willow grouse are hunted throughout its range, and regionally it is a game bird of great cultural and economical importance. Results: We sequenced 18 autosomal protein coding loci from approximately 15-18 individuals per population. We found a total of 127 SNP's, which corresponds to 1 SNP every 51 bp. 26 SNP's were amino acid replacement substitutions. Total nucleotide diversity (pi(t)) was between 1.30 x 10(-4) and 7.66 x 10(-3) (average pi(t) = 2.72 x 10(-3) +/- 2.06 x 10(-3)) and silent nucleotide diversity varied between 4.20 x 10(-4) and 2.76 x 10(-2) (average pi(S) = 9.22 x 10(-3) +/- 7.43 x 10(-4)). The synonymous diversity is approximately 20 times higher than in humans and two times higher than in chicken. Non-synonymous diversity was on average 18 times lower than the synonymous diversity and varied between 0 and 4.90 x 10(-3) (average pi(a) = 5.08 x 10(-4) +/- 7.43 x 10(3)), which suggest that purifying selection is strong in these genes. F-ST values based on synonymous SNP's varied between -5.60 x 10(-4) and 0.20 among loci and revealed low levels of differentiation among the four localities, with an overall value of F-ST = 0.03 (95% CI: 0.006 -0.057) over 60 unlinked loci. Non-synonymous SNP's gave similar results. Low levels of linkage disequilibrium were observed within genes, with an average r(2) = 0.084 +/- 0.110, which is expected for a large outbred population with no population differentiation. The mean per site per generation recombination parameter (rho) was comparably high (0.028 +/- 0.018), indicating high recombination rates in these genes. Conclusion: We found unusually high levels of nucleotide diversity in the Scandinavian willow grouse as well as very little population structure among localities with up to 1647 km distance. There are also low levels of linkage disequilibrium within the genes and the population recombination rate is high, which is indicative of an old panmictic population, where recombination has had time to break up any haplotype blocks. The non-synonymous nucleotide diversity is low compared with the silent, which is in agreement with effective purifying selection, possibly due to the large effective population size.
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| 9. |
- Besnier, Francois, et al.
(författare)
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A genetic algorithm based method for stringent haplotyping of family data
- 2009
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The linkage phase, or haplotype, is an extra level of information that in addition to genotype and pedigree can be useful for reconstructing the inheritance pattern of the alleles in a pedigree, and computing for example Identity By Descent probabilities. If a haplotype is provided, the precision of estimated IBD probabilities increases, as long as the haplotype is estimated without errors. It is therefore important to only use haplotypes that are strongly supported by the available data for IBD estimation, to avoid introducing new errors due to erroneous linkage phases.Results: We propose a genetic algorithm based method for haplotype estimation in family data that includes a stringency parameter. This allows the user to decide the error tolerance level when inferring parental origin of the alleles. This is a novel feature compared to existing methods for haplotype estimation. We show that using a high stringency produces haplotype data with few errors, whereas a low stringency provides haplotype estimates in most situations, but with an increased number of errors.Conclusion: By including a stringency criterion in our haplotyping method, the user is able to maintain the error rate at a suitable level for the particular study; one can select anything from haplotyped data with very small proportion of errors and a higher proportion of non-inferred haplotypes, to data with phase estimates for every marker, when haplotype errors are tolerable. Giving this choice makes the method more flexible and useful in a wide range of applications as it is able to fulfil different requirements regarding the tolerance for haplotype errors, or uncertain marker-phases.
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| 10. |
- Brunberg, Emma, et al.
(författare)
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A missense mutation in PMEL17 is associated with the Silver coat color in the horse
- 2006
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 7, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype. Results: Segregation data on the Silver locus (Z) were obtained within one half-sib family that consisted of a heterozygous Silver colored stallion with 34 offspring and their 29 non-Silver dams. We typed 41 genetic markers well spread over the horse genome, including one single microsatellite marker (TKY284) close to the candidate gene PMEL17 on horse chromosome 6 (ECA6q23). Significant linkage was found between the Silver phenotype and TKY284 (theta = 0, z = 9.0). DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys). This mutation showed complete association with the Silver phenotype across multiple horse breeds, and was not found among non-Silver horses with one clear exception; a chestnut colored individual that had several Silver offspring when mated to different non-Silver stallions also carried the exon 11 mutation. In total, 64 Silver horses from six breeds and 85 non-Silver horses from 14 breeds were tested for the exon 11 mutation. One additional mutation located in intron 9, only 759 bases from the missense mutation, also showed complete association with the Silver phenotype. However, as one could expect to find several non-causative mutations completely associated with the Silver mutation, we argue that the missense mutation is more likely to be causative. Conclusion: The present study shows that PMEL17 causes the Silver coat color in the horse and enable genetic testing for this trait.
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