Gerli Rosengren Pielberg

Publications of Gerli Rosengren Pielberg

• Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

  Authors: Amaury Vaysse, Abhirami Ratnakumar, Thomas Derrien, Erik Axelsson, Gerli Rosengren Pielberg, Snaevar Sigurdsson, Tove Fall, Eija H Seppälä, Mark S T Hansen, Cindy T Lawley [......] Carles Vilà, Hannes Lohi, Francis Galibert, Merete Fredholm, Jens Häggström, Ake Hedhammar, Catherine André, Kerstin Lindblad-Toh, Christophe Hitte, Matthew T Webster

  PLoS genetics. 10/2011; 7(10):e1002316.

  The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysisThe extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

• A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.

  Authors: Mia Olsson, Jennifer R S Meadows, Katarina Truvé, Gerli Rosengren Pielberg, Francesca Puppo, Evan Mauceli, Javier Quilez, Noriko Tonomura, Giordana Zanna, Maria José Docampo [......] Daniel L Kastner, Erik Bongcam-Rudloff, Matthew T Webster, Armand Sanchez, Ake Hedhammar, Elaine F Remmers, Leif Andersson, Lluis Ferrer, Linda Tintle, Kerstin Lindblad-Toh

  PLoS genetics. 03/2011; 7(3):e1001332.

  Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated inHereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 × 10⁻⁶, p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

• A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.

  Authors: Gerli Rosengren Pielberg, Anna Golovko, Elisabeth Sundström, Ino Curik, Johan Lennartsson, Monika H Seltenhammer, Thomas Druml, Matthew Binns, Carolyn Fitzsimmons, Gabriella Lindgren [......] Roswitha Baumung, Monika Vetterlein, Sara Strömberg, Manfred Grabherr, Claire Wade, Kerstin Lindblad-Toh, Fredrik Pontén, Carl-Henrik Heldin, Johann Sölkner, Leif Andersson

  Nature genetics. 08/2008; 40(8):1004-9.

  In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kbIn horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.

• Efficient mapping of mendelian traits in dogs through genome-wide association.

  Authors: Elinor K Karlsson, Izabella Baranowska, Claire M Wade, Nicolette H C Salmon Hillbertz, Michael C Zody, Nathan Anderson, Tara M Biagi, Nick Patterson, Gerli Rosengren Pielberg, Edward J Kulbokas, Kenine E Comstock, Evan T Keller, Jill P Mesirov, Henrik von Euler, Olle Kämpe, Ake Hedhammar, Eric S Lander, Göran Andersson, Leif Andersson, Kerstin Lindblad-Toh

  Nature genetics. 12/2007; 39(11):1321-8.

  With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array withWith several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.

• Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs.

  Authors: Nicolette H C Salmon Hillbertz, Magnus Isaksson, Elinor K Karlsson, Eva Hellmén, Gerli Rosengren Pielberg, Peter Savolainen, Claire M Wade, Henrik von Euler, Ulla Gustafson, Ake Hedhammar, Mats Nilsson, Kerstin Lindblad-Toh, Leif Andersson, Göran Andersson

  Nature genetics. 12/2007; 39(11):1318-20.

  The dorsal hair ridge in Rhodesian and Thai Ridgeback dogs is caused by a dominant mutation that also predisposes to the congenital developmental disorder dermoid sinus. Here we show that theThe dorsal hair ridge in Rhodesian and Thai Ridgeback dogs is caused by a dominant mutation that also predisposes to the congenital developmental disorder dermoid sinus. Here we show that the causative mutation is a 133-kb duplication involving three fibroblast growth factor (FGF) genes. FGFs play a crucial role in development, suggesting that the ridge and dermoid sinus are caused by dysregulation of one or more of the three FGF genes during development.