Chromosomal Localization, Embryonic Expression, and Imprinting Tests for Bmp7 on Distal Mouse Chromosome 2

Murine Bmp7 has been assigned to distal Chromosome 2 by interspecific backcross mapping. The map location suggests close linkage to classical mouse mutations and places Bmp7 within a chromosome region thought to contain one or more unidentified imprinted genes. A direct test suggests that Bmp7 is not imprinted. An examination of embryonic RNA expression patterns shows that Bmp7 is expressed in a variety of skeletal and nonskeletal tissues. Both embryonic expression patterns and the human chromosomal sublocalization inferred from its mouse location make Bmp7 a candidate for the gene affected in some patients with Holt-Oram syndrome.     

Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.     

Synthesis of fibronectin in normal and osteoarthritic articular cartilage

The content and the biosynthesis of fibronectin was examined in disease-free articular cartilage and in articular cartilage from osteoarthritic canine joints. Fibronectin content was increased in extracts of cartilage from osteoarthritic joints. Incubation of cartilage in vitro with [³H]phenylalanine and subsequent isolation of [³H]fibronectin from a gelatin affinity column and characterization by SDS-polyacrylamide gel electrophoresis and by immunoprecipitation indicated that disease-free and osteoarthritic cartilage explants synthesized fibronectin. About 50% of the [³H]fibronectin was recovered in the incubation medium. The osteoarthritic cartilage synthesized and accumulated up to 5-fold more [³H]fibronectin than disease-free cartilage.     

Genetic interaction between Non-MHC T- and B-cell alloantigens in response to rous sarcomas in chickens

Chickens of Regional Poultry Research Laboratory (RPRL) inbred line 6₃ regress sarcomas induced by Bryan high-titer Rous sarcoma virus to a greater extent than chickens of line RPRL 100, although these lines are identical for the major histocompatibility B complex. They differ, however, at three independent autosomal loci: Ly-4 and Th-1 determine the surface alloantigens of partly overlapping subsets of T lymphocytes, and Bu-1 determines a surface alloantigen of B lymphocytes. The association of genotypes at these loci with quantitative variation in their ability to regress Rous sarcomas was tested in segregating F₄ generation progeny derived from crosses of lines 100 and 6₃. The Ly-4 and Bu-1 genotypes showed association with Rous sarcoma regression, but the Th-1 genotype did not. Chickens of the Ly-4 ^a/Ly-4 ^a, Bu-1 ^b/Bu-1 ^b and Ly-4 ^b/Ly-4 ^b, Bu-1 ^a/Bu-1 ^a genotypes had a significantly higher regressor ability than the other two double homozygous genotypes. These results indicate that higher regression is associated with (1) interaction between the Ly-4 and Bu-1 loci, and (2) complementation between either the line 6 Ly-4 ^a allele and the line 100 Bu-1 ^b allele, or the line 100 Ly-4 ^b allele and the line 6 Bu-1 ^a allele.     

The stimulatory effect of testosterone propionate and 17β-estradiol on 5′-methylthioadenosine phosphorylase activity in rat target tissues

The effect of castration and subsequent administration of 17β-estradiol and testosterone propionate on 5′-methylthioadenosine phosphorylase activity in rat target tissues was studied. Castration 34 days earlier resulted in a 95 reduction in ventral prostate 5′-methylthioadenosine phosphorylase activity and 16 days earlier in a 67% reduction in uterine 5′-methylthiodenosine phosphorylase activity. Four days of testosterone propionate administration stimulated ventral prostate 5′-methylhioadenosine phosphorylase activity 32% above castrate levels, which represented more than 50% of the intact control levels. 17β-Estradiol on the other hand stimulated uterine 5′-methylthioadenosine phosphorylase activity of 35% above castrate controls within 24h and with 3 days of continuous hormone treatment to within 97% of the intact control levels. However, castration and subsequent 17β-estradiol administration did not affect 5′-methylthioadenosine phosphorylase activity in rat liver and lung. Both prostate and uterine 5′-methylthioadenosine phosphorylase were shown to metabolize 5′-methylthioadenosine to 5′-methylthioribose through a 5′-methythiribose 1-phosphate intermediate. The data suggest that 5′-methylthioadenosine is not allowed to accumulate in rat target tissues even under conditions which are known to stimulate polyamine synthesis.