A copy number variation morbidity map of developmental delay

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ～14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.     

Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations

We identified four girls with a consistent constellation of facial dysmorphism and malformations previously reported in a single mother-daughter pair. Toe syndactyly, telecanthus and anogenital and renal malformations were present in all affected individuals; thus, we propose the name 'STAR syndrome' for this disorder. Using array CGH, qPCR and sequence analysis, we found causative mutations in FAM58A on Xq28 in all affected individuals, suggesting an X-linked dominant inheritance pattern for this recognizable syndrome.     

Exposing the fitness contribution of duplicated genes

Duplicate genes from the whole-genome duplication (WGD) in yeast are often dispensable--removing one copy has little or no phenotypic consequence. It is unknown, however, whether such dispensability reflects insignificance of the ancestral function or compensation from paralogs. Here, using precise competition-based measurements of the fitness cost of single and double deletions, we estimate the exposed fitness contribution of WGD duplicate genes in metabolism and bound the importance of their ancestral pre-duplication function. We find that the functional overlap between paralogs sufficiently explains the apparent dispensability of individual WGD genes. Furthermore, the lower bound on the fitness value of the ancestral function, which is estimated by the degree of synergistic epistasis, is at least as large as the average fitness cost of deleting single non-WGD genes. These results suggest that most metabolic functions encoded by WGD genes are important today and were also important at the time of duplication.     

Genetic activity of mouse oocytes during in vitro "spontaneous" maturation]

Mouse oocytes, liberated from ovarian follicles, resume meiosis in the obligatory presence of Ca++. PHMPS exerts a toxic effect on this mechanism. m-RNA synthesis, in contrast to that of r-RNA. seems to be required during the first hours of maturation in order to ensure realization of the following steps: in addition the 2nd maturation period, corresponding to the first polar body extrusion, depends on the presence of proteins synthesized during the chromatin condensation process and germinal vesicle breakdown. We suggest that it might be a factor responsible for microtubule formation in metaphase I.     

Range of the Brown-headed Cowbird in Colorado: past and present

The historic range of the bison ( Bison bison ) on the Great Plains has been well documented. In Colorado the range of bison included both the eastern grasslands and higher-elevation ridges and mountain parks, up to an elevation of 3900 m. Based on the commensal relationship of the brood-parasitic Brown-headed Cowbird ( Molothrus ater ) with the bison, we suggest that the cowbird had a larger historical elevational range in Colorado than previously known and consequently has had a long-term host-parasite relationship with high-elevation breeding songbirds.     

Evidence for neuromelanin involvement in MPTP-induced neurotoxicity

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine, which has a high affinity for melanins. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.     

The early statistical interpretations of quantum mechanics in the USA and USSR

This article is devoted to the statistical (ensemble) interpretations of quantum mechanics which appeared in the USA and USSR before War II and in the early war years. The author emphasizes a remarkable similarity between the statements which arose in different scientific, philosophical, and even political contexts. The comparative analysis extends to the scientific and philosophical traditions which lay behind the American and Soviet statistical interpretations of quantum mechanics.The author insists that the philosophy of quantum mechanics is an autonomous branch rather than an applied philosophy or philosophical physics.