Human subtelomeres are polymorphic patchworks of inter-chromosomal segmental duplications at the ends of chromosomes. We provide evidence here that these patchworks arose recently through repeated translocations between chromosome ends. We assess the relative contribution of the major modes of ectopic DNA repair to the formation of subtelomeric duplications and find that nonhomologous end-joining predominates. Once subtelomeric duplications arise, they are prone to homology-based sequence transfers as evidenced by incongruent phylogenetic relationships of neighboring sections. Inter-chromosomal recombination of subtelomeres is a potent force for recent change. Cytogenetic and sequence analyses reveal that pieces of the subtelomeric patchwork changed location and copy number during primate evolution with unprecedented frequency. Half of known subtelomeric sequence formed recently through human-specific sequence transfers and duplications. Subtelomeric dynamics result in a gene-duplication rate significantly higher than the genome average and could have both advantageous and pathological consequences in human biology. More generally, our analyses suggest an evolutionary cycle between segmental polymorphisms and genome rearrangements.The human genome contains an abundance of large DNA segments that duplicated during the last 40 million years 1,2 . These segmental duplications (SDs) represent ≥5% of the genome 2 and are found frequently near centromeres and telomeres 3 . SDs are emerging as significant factors in chromosomal rearrangements leading to disease 4 and rapid gene innovation 2 , but the mechanisms by which they form are not well understood. Here, we focus on the unusually dense concentrations of inter-chromosomal SDs comprising human subtelomeres, which form the transition zones between chromosome-specific sequence and the arrays of telomeric repeats capping each chromosomal end. Previous cytogenetic studies showed that human subtelomeres are strikingly polymorphic in content -large segments can be present in or absent from normal alleles 5 -and that copy number of subtelomeric segments can vary among higher primates 6-9 . This natural plasticity combined with documented expression of several human subtelomeric genes 10,11 suggests that the evolutionary dynamics of subtelomeric regions could contributeCorrespondence and requests for materials should be addressed to B.J.T. (e-mail: btrask@fhcrc.org Complex inter-related structuresOur "paralogy map" of subtelomeric SDs (Fig. 1, Table S1) uses all finished sequences of genomic clones submitted to GenBank before April 2003. The map comprises ~2.6 Mbp of sequence present in two or more of 33 human subtelomeres (including three allelic pairs). The seven completely sequenced subtelomeres in the set are bounded distally by 0.5-2.4 kbp of various tandemly repeated units 13 called telomere-associated repeats (TAR1) and a short sample of the native telomeric arrays 14 . Numerous degenerate telomere-like repeats and TAR1 elements are also situated at varying...

We sought to biologically characterize and identify a subpopulation of urine-derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages.When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic, and neurogenic lineages but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction.

Spinocerebellar ataxia type 7 (SCA7) is characterized by cone-rod dystrophy retinal degeneration and is caused by a polyglutamine [poly(Q)] expansion within ataxin-7, a protein of previously unknown function. Here, we report that ataxin-7 is an integral component of the mammalian STAGA (SPT3-TAF9-ADA-GCN5 acetyltransferase) transcription coactivator complex, interacts directly with the GCN5 histone acetyltransferase component of STAGA, and mediates a direct interaction of STAGA with the CRX (cone-rod homeobox) transactivator of photoreceptor genes. Consistent with these results, chromatin immunoprecipitation assays document retinal-specific association of CRX, GCN5, and acetylated histone H3 with CRX target genes. RNA interference studies also implicate ataxin-7 and GCN5 in CRX-dependent gene activation, and histone deacetylase inhibitors restore the compromised expression of a CRX target gene in an ataxin-7-deficient background. Significantly, in relation to SCA7, poly(Q)-expanded ataxin-7 gets incorporated into STAGA and, in a dominant-negative manner, inhibits the nucleosomal histone acetylation function of STAGA GCN5 both in vitro and, based on chromatin immunoprecipitation assays, in SCA7 transgenic mice. These results suggest that the normal function of a poly(Q) disease protein may intersect with its pathogenic mechanism, an observation with significant implications for the molecular basis of all poly(Q) disorders and ultimately for their treatment.SCA7 ͉ transcription ͉ neurodegeneration ͉ poly(Q) ͉ CRX

There is compelling evidence for the role of the leucine-rich repeat kinase 2 (LRRK2) and in particular its kinase function in Parkinson's disease. Orally bioavailable, brain penetrant and potent LRRK2 kinase inhibitors are in the later stages of clinical development. Here, we describe a facile and robust assay to quantify LRRK2 kinase pathway activity by measuring LRRK2-mediated phosphorylation of Rab10 in human peripheral blood neutrophils. We use the selective MJFF-pRab10 monoclonal antibody recognising the Rab10 Thr73 phospho-epitope that is phosphorylated by LRRK2. We highlight the feasibility and practicability of using our assay in the clinical setting by studying a few patients with G2019S LRRK2 associated and sporadic Parkinson's as well as healthy controls. We suggest that peripheral blood neutrophils are a valuable resource for LRRK2 research and should be considered for inclusion in Parkinson's bio-repository collections as they are abundant, homogenous and express relatively high levels of LRRK2 as well as Rab10. In contrast, the widely used peripheral blood mononuclear cells are heterogeneous and only a minority of cells (monocytes and contaminating neutrophils) express LRRK2. While our LRRK2 kinase pathway assay could assist in patient stratification based on LRRK2 kinase activity, we envision that it may find greater utility in pharmacodynamic and target engagement studies in future LRRK2 inhibitor trials.

Background: Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage. Methods: In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks' gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH + TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5 £ TSH < 5.22 or 5.22 £ TSH < 10 respectively). Accordingly, the SCH + TAI group was also stratified into two subgroups (SCH + TAI 1 and SCH + TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks. Results: Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. .28]; p = 0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13 -3.21 weeks with subclinical thyroid abnormalities vs. 9.33 -1.71 weeks with ET; p = 0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH + TAI (SCH 1 vs. SCH 2: 10.79 -1.77 vs. 9.70 -1.47 weeks, p = 0.039; SCH + TAI 1 vs. SCH + TAI 2: 9.59 -1.97 vs. 8.88 -1.24 weeks, p = 0.031). Conclusions: Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage.

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Mutations in the beta-synuclein gene may predispose to DLB.

Lower motor neuron degeneration in ALS is a focal process that advances contiguously, summates over time, and creates graded loss. Stage of degeneration in the nervous system is a function of anatomic location.