The promises and problems of linkage analysis by using the current canine genome map

There have been major advances in the canine genome map over recent years, with an agreed karyotype for all 38 pairs of autosomes and an integrated linkage-radiation-hybrid map now available. An individual dog breed represents a closed, isolated population, and many suffer genetic diseases. Some are homologs of human conditions, and dogs represent naturally occurring, potentially useful large mammal models. Other conditions may be unique to this species, but study of these offers new insights into metabolic pathways. Linkage analysis may identify a locus linked to a particular condition. Dog pedigrees facilitate these studies by being relatively more informative than human families, although planned breeding strategies to maximize the informativeness may be required. A study of a late-onset, acquired heart disease, dilated cardiomyopathy (DCM), in Newfoundland dogs highlights some of the problems. The disease occurs naturally in pedigrees within the UK in dogs kept as pets and breeding stock. Problems encountered include confirmation of the mode of inheritance and determination of phenotype. A genome-wide linkage analysis study with over 200 markers failed to detect linkage. The study indicates that more detailed linkage maps are required, and further synteny information between dog and human gained before study of diseases affecting naturally occurring families of dogs from inbred pedigrees may have maximal chance of success in order to utilize this model

Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain

Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino-terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy. We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (Delta Q) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution, the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in a-helix structure, while deletion of the repeat resulted in a small loss of a-helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte trimethylamine N-oxide. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after the deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition, this polypeptide not only showed enhanced binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonic acid but was more sensitive to urea-induced unfolding. Taken together, these findings support the view that the presence and length of the poly-Q repeat modulate the folding and structure of the AR-NT

Topological dynamics of an intrinsically disordered N‐terminal domain of the human androgen receptor

Analytical BioScience

Y-chromosomal haplogroups from wild and domestic goats reveal ancient migrations and recent introgressions

By its paternal transmission, Y-chromosomal haplotypes are sensitive markers of population history and male-mediated introgression. We used whole-genome sequences (WGSs) of 386 domestic goats from 75 modern breeds and 7 wild goat species generated by the VarGoats goat genome project. Phylogenetic analyses indicated five domestic haplogroups Y1AA, Y1AB, Y1B, Y2A and Y2B. Haplogroup distributions for 180 domestic breeds indicate ancient paternal population bottlenecks during the migration into northern Europe, southern Asia and Africa. Sharing of haplogroups reveals male-mediated introgressions: from Asia into Madagascar and, more recently, into the South-African Boer goat; then from this breed into other southeastern African goats; and from Europe into native Korean and Ugandan goats. This study illustrates the power of the Y-chromosomal variation for the reconstructing the history of domestic species with a wide geographic range