| 1. |
- Kalnina, Ineta, et al.
(författare)
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Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes
- 2013
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 527:2, s. 462-468
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Tidskriftsartikel (refereegranskat)abstract
- Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.
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| 2. |
- Krishnan, Arunkumar, et al.
(författare)
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Remarkable similarities between the hemichordate (Saccoglossus kowalevskii) and vertebrate GPCR repertoire
- 2013
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 526:2, s. 122-133
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Tidskriftsartikel (refereegranskat)abstract
- Saccoglossus kowalevskii (the acorn worm) is a hemichordate belonging to the superphylum of deuterostome bilateral animals. Hemichordates are sister group to echinoderms, and closely related to chordates. S. kowalevskii has chordate like morphological traits and serves as an important model organism, helping developmental biologists to understand the evolution of the central nervous system (CNS). Despite being such an important model organism, the signalling system repertoire of the largest family of integral transmembrane receptor proteins, G protein-coupled receptors (GPCRs) is largely unknown in S. kowalevskii. Here, we identified 260 unique GPCRs and classified as many as 257 of them into five main mammalian GPCR families; Glutamate (23), Rhodopsin (212), Adhesion (18), Frizzled (3) and Secretin (1). Despite having a diffuse nervous system, the acorn worm contains well conserved orthologues for human Adhesion and Glutamate family members, with a similar N-terminal domain architecture. This is particularly true for genes involved in CNS development and regulation in vertebrates. The average sequence identity between the GPCR orthologues in human and S. kowalevskii is around 47%, and this is same as observed in couple of the closest vertebrate relatives, Ciona intestinalis (41%) and Branchiostoma floridae (similar to 47%). The Rhodopsin family has fewer members than vertebrates and lacks clear homologues for 6 of the 13 subgroups, including olfactory, chemokine, prostaglandin, purine, melanocyte concentrating hormone receptors and MAS-related receptors. However, the peptide and somatostatin binding receptors have expanded locally in the acorn worm. Overall, this study is the first large scale analysis of a major signalling gene superfamily in the hemichordate lineage. The establishment of orthologue relationships with genes involved in neurotransmission and development of the CNS in vertebrates provides a foundation for understanding the evolution of signal transduction and allows for further investigation of the hemichordate neurobiology.
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| 3. |
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| 4. |
- Sällman Almén, Markus, et al.
(författare)
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Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children.
- 2013
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 37:3, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- Background:The Fat mass and obesity-associated gene (FTO) was the first gene reliably associated with body mass index in genome-wide association studies on a population level. At present, the genetic variations within the FTO gene are still the common variants that have the largest influence on body mass index.Methods:In the current study, we amplified the entire FTO gene, in total 412 Kbp, in over 200 long-range PCR fragments from each individual, from 524 severely obese and 527 lean Swedish children, and sequenced the products as two DNA pools using massive parallel sequencing (SOLiD).Results:The sequencing achieved very high coverage (median 18 000 reads) and we detected and estimated allele frequencies for 705 single nucleotide polymorphisms (SNPs) (19 novel) and 40 indels (24 novel) using a sophisticated statistical approach to remove false-positive SNPs. We identified 19 obesity-associated SNPs within intron one of the FTO gene, and validated our findings with genotyping. Ten of the validated obesity-associated SNPs have a stronger obesity association (P<0.007) than the commonly studied rs9939609 SNP (P<0.012).Conclusions:This study provides a comprehensive obesity-associated variation map of FTO, identifies novel lead SNPs and evaluates putative causative variants. We conclude that intron one is the only region within the FTO gene associated with obesity, and finally, we establish next generation sequencing of pooled DNA as a powerful method to investigate genetic association with complex diseases and traits.
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| 5. |
- Valsalan, Ravisankar, et al.
(författare)
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Early vertebrate origin of melanocortin 2 receptor accessory proteins (MRAPs)
- 2013
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Ingår i: General and Comparative Endocrinology. - : Elsevier BV. - 0016-6480 .- 1095-6840. ; 188, s. 123-132
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Tidskriftsartikel (refereegranskat)abstract
- The melanocortin 2 receptor (MC2R) accessory proteins, MRAP, along with its homolog, MRAP2, are two among a growing number of G protein-coupled receptor accessory proteins that have been identified in recent years. These proteins interact directly with MC2R and are essential for trafficking of this receptor from the endoplasmic reticulum to the cell surface, where it mediates the effects of ACTH. lthough earlier studies have identified MRAP and MRAP2 subtypes in distant species, an overall evolutionary analysis of these families is still missing. Here, we performed a comprehensive evolutionary analysis of the MRAP and MRAP2 homologs based on whole genome sequences. We systematically mined and analyzed the genomes of metazoans to identify these genes. Overall, we identified 70 sequences of MRAP and MRAP2 from 44 species belonging to several vertebrate lineages, including at least 40 new sequences previously not reported in the literature. Herein, we provide evidence that MRAP2 is likely to be the ancestor of the MRAP family because MRAP2-like protein, but not MRAP, was identified in Petromyzon marinus (sea lamprey), which belong to an ancient basal vertebrate lineage. Later in vertebrate evolution, MRAP2 duplicated and gave rise to MRAP in an event before the emergence of actinopterygii (ray-finned fishes). However, we observed losses of MRAP in sarcopterygii (lobe-finned fish), amphibians and reptiles while both subtypes are present in chicken and most mammals studied. Synteny analysis showed a conserved synteny within same lineages and an inversion of gene order between lineages. An evolutionary rate shift analysis indicated that these genes were under high purifying selection. Overall, this study provides a comprehensive analysis of the evolution and gene repertoire of MRAP and MRAP2.
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| 6. |
- Zheleznyakova, Galina Y., et al.
(författare)
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Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:9, s. 988-993
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Tidskriftsartikel (refereegranskat)abstract
- Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.
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