Phenotypic heterogeneity in lymphoblastic cell lines

Four T-cell and two B-cell lines from patients with lymphoblastic leukemia were examined with a panel of monoclonal antibodies for a variety of lineage and differentiation stage-associated antigens during growth in liquid suspension. In five of the lines, markers normally associated with the granulopoietic lineage were found and the level of expression of these markers varied during culture. The sixth line, MOLT-3, was examined in more detail. Using clonal selection it was found that phenotypic heterogeneity could readily be obtained and that subclones could be acquired that expressed a wide range of markers, typically in reproducible kinetic patterns, that were not detected on the parent clone. Previous results were confirmed showing that treatment with the drug 5-azacytidine (5-aza) prior to selection promoted the expression of the granulopoietic lineage associated antigen 80H.5 on MOLT-3 subclones; however, treatment with 5-aza appeared to inhibit substantially the expression of other novel markers by subclones following a second selection compared to untreated controls. It appears that the expression of markers normally associated with other lineages on leukemic lymphoblasts (lineage infidelity) may be characteristic of such lines and that phenotypically variant subclones expressing lineage infidelity can readily be obtained by clonal selection.     

Brachygnathia,cardiomegaly and renal hypoplasia syndrome (BCRHS) in Merino sheep maps to a 1.1‐megabase region on ovine chromosome OAR2

A genome scan was conducted to map the autosomal recessive lethal disorder brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS) in Poll Merino sheep. The scan involved 10 affected and 27 unaffected animals from a single Poll Merino/Merino sheep flock, which were genotyped with the Illumina Ovine SNP50 BeadChip. Association and homozygosity mapping analyses located the disorder in a region comprising 20 consecutive SNPs spanning 1.1 Mb towards the distal end of chromosome OAR2. All affected animals and none of the unaffected animals were homozygous for the associated haplotype in this region. These results provide the basis for identifying the causative mutation(s) and should enable the development of a DNA test to identify carriers in the Poll Merino sheep population. Understanding the molecular control of BCRHS may provide insight into the fundamental genetic control and regulation of the affected organ systems.     

Evidence for pleiotropism and recent selection in the PLAG1 region in Australian Beef cattle

A putative functional mutation (rs109231213) near PLAG1 (BTA14) associated with stature was studied in beef cattle. Data from 8199 Bos taurus, Bos indicus and Tropical Composite cattle were used to test the associations between rs109231213 and various phenotypes. Further, 23 496 SNPs located on BTA14 were tested for association with these phenotypes, both independently and fitted together with rs109231213. The C allele of rs109231213 significantly increased hip height, weight, net food intake, age at puberty in males and females and decreased IGF‐I concentration in blood and fat depth. When rs109231213 was fitted as a fixed effect in the model, there was an overall reduction in associations between other SNPs and these traits but some SNPs remained associated (P < 10^?4). Frequency of the mutant C allele of rs109231213 differed among B. indicus (0.52), B. taurus (0.96) and Tropical Composite (0.68). Most chromosomes carrying the C allele had the same surrounding 10 SNP haplotype, probably because the C allele was introgressed into Brahman from B. taurus cattle. A region of reduced heterozygosity surrounds the C allele; this is small in B. taurus but 20 Mb long in Brahmans, indicating recent and strong selection for the mutant allele. Thus, the C allele appears to mark a mutation that has been selected almost to fixation in the B. taurus breeds studied here and introduced into Brahman cattle during grading up and selected to a frequency of 0.52 despite its negative effects on fertility.