The birth of a human-specific neural gene by incomplete duplication and gene fusion

Background: Gene innovation by duplication is a fundamental evolutionary process but is difficult to study in humans due to the large size, high sequence identity, and mosaic nature of segmental duplication blocks. The human-specific gene hydrocephalus-inducing 2, HYDIN2, was generated by a 364 kbp duplication of 79 internal exons of the large ciliary gene HYDIN from chromosome 16q22.2 to chromosome 1q21.1. Because the HYDIN2 locus lacks the ancestral promoter and seven terminal exons of the progenitor gene, we sought to characterize transcription at this locus by coupling reverse transcription polymerase chain reaction and long-read sequencing. Results: 5' RACE indicates a transcription start site for HYDIN2 outside of the duplication and we observe fusion transcripts spanning both the 5' and 3' breakpoints. We observe extensive splicing diversity leading to the formation of altered open reading frames (ORFs) that appear to be under relaxed selection. We show that HYDIN2 adopted a new promoter that drives an altered pattern of expression, with highest levels in neural tissues. We estimate that the HYDIN duplication occurred ~3.2 million years ago and find that it is nearly fixed (99.9%) for diploid copy number in contemporary humans. Examination of 73 chromosome 1q21 rearrangement patients reveals that HYDIN2 is deleted or duplicated in most cases. Conclusions: Together, these data support a model of rapid gene innovation by fusion of incomplete segmental duplications, altered tissue expression, and potential subfunctionalization or neofunctionalization of HYDIN2 early in the evolution of the Homo lineage

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis

Lymph node dendritic cells harbor inducible replication-competent HIV despite years of suppressive ART.

Although gut and lymph node (LN) memory CD4 T cells represent major HIV and simian immunodeficiency virus (SIV) tissue reservoirs, the study of the role of dendritic cells (DCs) in HIV persistence has long been limited to the blood due to difficulties to access lymphoid tissue samples. In this study, we show that LN migratory and resident DC subpopulations harbor distinct phenotypic and transcriptomic profiles. Interestingly, both LN DC subpopulations contain HIV intact provirus and inducible replication-competent HIV despite the expression of the antiviral restriction factor SAMHD1. Notably, LN DC subpopulations isolated from HIV-infected individuals treated for up to 14 years are transcriptionally silent but harbor replication-competent virus that can be induced upon TLR7/8 stimulation. Taken together, these results uncover a potential important contribution of LN DCs to HIV infection in the presence of ART

Evaluation of the water quality of tidal creeks of Pontal do Paraná, Paraná, Brazil

The aim of this wat was to evaluate the water quality in four tidal creeks of Paraná, Brazil, with different anthropic influences. Samples were collected every three months. Temperature, salinity, pH, alkalinity, total CO2, dissolved O2, nitrite, nitrate, N-ammoniacal, phosphate, silicate, particulate suspended matter, humic matter, total chlorophyll, total and fecal coliform bacteria of surface water were measured in each sample and compared. For all the stations water temperature was lower in winter, but ranged within typically subtropical values. Salinity (7 - 25) and pH (7.08 - 7.91) were higher in Perequê tidal creek indicating that only this tidal creek was strongly influenced by the nearby ocean waters. Lower dissolved O2, reaching anoxic levels along with higher phosphate and N-ammoniacal concentrations and higher total (<200 - 160,000 MPN 100 ml-1) and thermotolerant coliforms (<200 - 50,000 MPN 100 ml-1) in Olho d´Água suggested euthrophication, especially in summer when rainfall was higher and tourism was at its peak. Perequê, Penedo and Barranco Creeks were characterized as meso- and oligotrophic environments.<br>Foi objetivo da presente pesquisa, avaliar a qualidade da água de quatro gamboas do Paraná, Brasil, que sofrem influências antrópicas distintas. Em cinco coletas trimestrais, foram obtidas, as seguintes variáveis em águas superficiais: temperatura, salinidade, pH, alcalinidade, dióxido de carbono, oxigênio dissolvido, nitrito, nitrato, N-amoniacal, fosfato, silicato, material particulado em suspensão, substâncias húmicas, clorofila total, coliformes totais e coliformes termotolerantes. Os resultados mostraram que a temperatura da água apresentou características tipicamente subtropicais com valores significativamente menores no inverno em todas as estações. A salinidade (7 - 25‰) e o pH (7,08 - 7,91) mais elevados, registrados na Gamboa Perequê, indicaram que somente este curso d´água é influenciado pelo mar adjacente. As quantidades baixas de oxigênio dissolvido, chegando a anoxia, altas de fosfato (8,11 - 208,11 µM), N-amoniacal (0,90 - 75,33 µM), coliformes totais (<200 - 160.000 NMP 100 mL-1) e coliformes termotolerantes (<200 - 50.000 NMP 100 mL-1) observadas na Gamboa Olho d´Água indicam que esta apresenta características típicas de eutrofização, principalmente no verão, época de maior pluviosidade e maior fluxo de turistas na região. As gamboas Perequê, Penedo e Barranco podem ser caracterizadas como gamboas meso- e oligotróficas