| 1. |
- Farias, Fabiana H. G., et al.
(författare)
-
A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers
- 2011
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 42:3, s. 468-474
-
Tidskriftsartikel (refereegranskat)abstract
- A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations: however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.
|
|
| 2. |
- Klütsch, Cornelya, et al.
(författare)
-
Segregation of point mutation heteroplasmy in the control region of dog mtDNA studied systematically in deep generation pedigrees
- 2011
-
Ingår i: International journal of legal medicine. - : Springer Science and Business Media LLC. - 0937-9827 .- 1437-1596. ; 125:4, s. 527-535
-
Tidskriftsartikel (refereegranskat)abstract
- Heteroplasmy, the presence of two or more variants in an organism, may render mitochondrial DNA (mtDNA)-based individual identification challenging in forensic analysis. However, the variation of heteroplasmic proportions and the segregation of heteroplasmic variants through generations and within families have not been systematically described at a large scale in animals such as the domestic dog. Therefore, we performed the largest study to date in domestic dogs and screened a 582-bp-long fragment of the mtDNA control region in 180 individuals in 58 pedigrees for signs of heteroplasmy. We identified three pedigrees (5.17%) with heteroplasmic point mutations. To follow the segregation of the point mutations, we then analyzed 131 samples from these three independent pedigrees and found significant differences in heteroplasmy between generations and among siblings. Frequently (10% of cases), the proportion of one base changed from 0-10% to 80-90% (as judged from Sanger electropherograms) between generations and varied to a similar extent among siblings. We included also a literature review of heteroplasmic and potential mutational hot spot positions in the studied region which showed that all heteroplasmic positions appear to be mutational hot spots. Thus, although heteroplasmy may be used to increase the significance of a match in forensic case work, it may also cause erroneous exclusion of related individuals because of sharp switches from one state to the other within a single generation or among siblings especially in the presented mutational hot spots.
|
|
| 3. |
- Vaysse, Amaury, et al.
(författare)
-
Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping
- 2011
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:10, s. e1002316-
-
Tidskriftsartikel (refereegranskat)abstract
- 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 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.
|
|
