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.     

Children and marital satisfaction in a non-Western sample: having more children increases marital satisfaction among the Igbo people of Nigeria

Previous research has demonstrated that having more children decreases marital satisfaction among parents. However, the universality of these findings is limited since the vast majority of the studies have been conducted in Western countries. In the present study, 374 people from the Igbo ethnic group (Nigeria) were assessed for levels of marital satisfaction and the number of children. In contrast to almost all previous findings, we found a positive relationship between the number of children and marital satisfaction among parents. Number of children was the strongest predictor of marital satisfaction even when compared to other variables like wealth and education. Our results suggest that the negative relationship between the number of children and marital satisfaction is not culturally universal and probably only characterizes developed, individualistic Western countries. We discuss our findings from a sociocultural and evolutionary perspective.     

Where ichthyofaunal provinces meet: the fish fauna of the Lake Edward system,East Africa

Based on literature, museum collections and three recent expeditions, an annotated species list of the Lake Edward, East Africa, drainage system is presented, excluding the endemic haplochromines. A total of 34 non-Haplochromis species belonging to 10 families and 21 genera are recorded from the system. Three of these are endemic and two others have been introduced in the region. Six species are new records for the Lake Edward system. A species accumulation curve indicates that we probably covered most of the non-Haplochromis species in the area sampled during the recent expeditions, but undetected species might still be present in the Congolese part of the system, which is poorly sampled. A comparison of the species list with those of neighbouring basins confirmed the placement of the Lake Edward system within the east-coast ichthyofaunal province.     

Modelling ultraviolet exposures in a school environment.

A technique has been developed to represent erythemally effective ultraviolet radiation exposure within a school environment. The technique models the erythemally effective exposure onto a horizontal plane representation of a mapped school environment located in Hervey Bay (25 degrees S, 153 degrees E), Australia. The input parameters used to model the ultraviolet exposures received within the school playground included the measured sky view, ground albedo and standing surface albedo. Estimates of the erythemally effective ultraviolet exposure received within the school playground during morning tea and lunch time meal breaks during a winter and summer school day are presented. The influence of tree shade and building structure was found to vary significantly with solar zenith angle modelled over the winter and summer school meal break times with horizontal plane exposures predicted to vary from between 0 and 7 SED at different locations within the playground. The technique presented provides a method that can be followed to examine the effect of surrounding buildings and surface structures of real environments on the predicted horizontal plane ultraviolet exposure.     

Pyridine nucleotide analog interference with metabolic processes in mitogen-stimulated human T lymphocytes

The differential metabolic effects of three nicotinamide analogs, 6-aminonicotinamide, 3-aminobenzamide, and 5-methylnicotinamide, were analyzed in mitogen-stimulated preparations of human T lymphocytes. Mitogen stimulation with the phorbol ester TPA and a monoclonal antibody to the T3 cell surface antigen caused an increase in cellular NAD and ATP levels and a marked increase in glucose metabolism as demonstrated by an increase in cellular levels of glucose 6-phosphate and a sevenfold increase in radioactive CO2 formation from [l-14C]glucose. 6-Aminonicotinamide had drastic inhibitory effects on the mitogen-stimulated increases in NAD and ATP levels as well as on the metabolism of glucose. Treatment of the mitogen-stimulated cells with 6-aminonicotinamide also caused a marked increase in cellular levels of 6-phosphogluconate, suggesting inhibition of the hexose monophosphate shunt at 6-phosphogluconate dehydrogenase. Radioactive CO2 formation from [6-14C]glucose showed that metabolism through the tricarboxylic acid cycle was not used to compensate for the inhibition of the hexose monophosphate shunt pathway. Treatment of cells with 3-aminobenzamide had the opposite effect of 6-aminonicotinamide in that cellular NAD levels increased, presumable due to inhibition of poly(ADP-ribose) polymerase. 3-Aminobenzamide did not interfere with ATP or glucose 6-phosphate levels and did not cause significant elevations of 6-phosphogluconate. Thus, 6-aminonicotinamide appears to have direct inhibitory effects on the synthesis of both pyridine nucleotides and poly(ADP-ribose), whereas 3-aminobenzamide has its major inhibitory effect on poly(ADP-ribose) synthesis. 5-Methylnicotinamide also interferes with the mitogen-stimulated increase in NAD levels but not as effectively as 6-aminonicotinamide. The alterations in pyridine nucleotide metabolism resulting from treatment with these nicotinamide analogs can produce drastic and diverse alterations in pathways of glucose utilization and energy generation.     

Molecular cloning of cDNA for human prostatic acid phosphatase

A human liver cDNA library in λgt11 was screened with polyclonal antiserum to human acid phosphatase isoenzyme 2a/4. About eleven positive clones have been obtained. Two clones, λ Hap21 and λ Hap22 were further characterized: clone λHap21 contained a 0.8-kb cDNA insert and clone λHap22 a 1.8–2.0-kb insert. XbaI digestion of λHap22 generated two fragments of 1.0 and 0.9 kb. BglII digestion resulted in a 1.2-kb fragment and several smaller fragments of undetermined size. Clone 1 Hap22 contained all the genes carried by λ gt11(lac 5cI857nin 5Sam 100) and the 2-kb insert. An Escherichia coli(λHap22) lysogen was generated, and its acid phosphatase activity was approximately ten-fold higher than that in the control nonlysogenic lysate. Western-blot analysis of total proteins present in this E. coli(λHap22) lysate revealed that the non-induced λHap22 prophage directed the synthesis of an approx. 175-kDa protein. This protein was recognized by antibody to the human acid phosphatase isoenzyme 2a/4 and anti-β-galactosidase and was produced only upon induction with IPTG. These results indicated that AHap22 carried a major portion of the gene coding for the human acid phosphatase isoenzyme 2a and/or 4 and this protein fragment of acid phosphatase was sufficient to manifest enzymatic activity.