Genetic defect may cause rare movement disorders

A Massachusetts General Hospital (MGH)-led research team has found that a defect in transcription of the TAF1 gene may be the cause of X-linked dystonia parkinsonism (XDP), a rare and severe neurodegenerative disease. Symptoms begin around age 40 with dystonia-involuntary muscle contractions that can force the body into abnormal, sometimes twisted positions and eventually proceed to Parkinson's-like symptoms, such as slowness of movement and a shuffling gait. Patients become progressively more disabled as the disease progresses and often die from complications such as infections or pneumonia.

Individuals with XDP share seven DNA sequence changes, which cluster within a region of the X-chromosome that includes the TAF1 gene. These sequence changes have always appeared to be inherited together. The largest genomics study ever performed for XDP, analyzing a total of 792 DNA samples from individuals with XDP and their unaffected relatives, as well as historical samples from studies dating back to the initial descriptions of the disease.

The analysis of these samples revealed a far greater genetic diversity among XDP patients than was previously known. While most shared a total of 54 unique sequence changes in a collection of variants known as a haplotype, in some individuals the haplotype had been broken apart due to genetic recombination. By comparing these recombination events, it was possible to narrow the disease-causing genomic segment to a smaller region that contained only the TAF1 gene.

Researchers reprogramed skin cells from patients with XDP and their healthy relatives back into stem cells, which differentiated into neural progenitor cells and then mature neurons. The team used RNA sequencing to characterize TAF1 expression patterns and found a defect in how the DNA sequence is transcribed into RNA in neural cells from XDP patients. In those cells, a portion of the TAF1 RNA appeared to terminate prematurely, which reduced expression of the full-length RNA. The truncated TAF1 RNA ended close to a known XDP-specific sequence variants - a large DNA insertion known as a retrotransposon.

 To determine whether the retrotransposon caused the transcriptional defect, t used genome they used editing tools to remove the sequence, which restored RNA transcription and normalized TAF1 expression. In a separate study, they analyzed the sequence of the retrotransposon in patients with XDP and found that it contained a segment of repetitive DNA that was longer in patients who developed symptoms at an earlier age and shorter in those whose symptoms appeared later.
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HIV-1 genetic diversity is higher in vaginal tract than in blood

The genetic diversity of human immunodeficiency virus type 1 (HIV-1) is higher in the vaginal tract than in the blood stream during early infection. When HIV-1 is transmitted from a man to a woman via intercourse, it must penetrate and infect various vaginal layers before reaching the blood.

Previous research has shown that, within a patient, systemic infection is usually established by a single genetic variant of HIV-1 in the blood. However, scientists hypothesize, the vaginal tract may initially harbor a genetically diverse HIV-1 population that is then filtered down to a single variant along the path to the blood stream.

Katja Klein of the University of Western Ontario, Canada, and colleagues conducted the first study to compare HIV-1 genetic diversity between the vaginal tract and the blood in newly infected people. They collected and applied next-generation deep sequencing to HIV-1 viruses isolated from the vaginal tract and blood plasma of women within seven months of infection.

This analysis revealed that each patient's vaginal tract generally harbored a diverse range of HIV-1 genetic variants (a mean of 5.7), while the blood had much lower genetic diversity (a mean of 1.7 variants). These results held true regardless of a patient's HIV-1 subtype, use of hormonal contraceptives, or number of sex acts or partners.

All samples in the study were collected at least one month after initial infection, and the researchers acknowledge the possibility that genetic diversity in the vaginal tract may have arisen post-infection. However, they point out that this is unlikely, given that similar diversification was not seen in the blood stream.

These findings present new evidence in support of the idea that a genetic bottleneck winnows out many genetic variants of HIV-1 between the vaginal tract and the blood during early infection. This could improve understanding of the transmission process, thereby informing efforts to develop vaccines and other therapies to prevent against HIV-1 infection.

Like many infectious pathogens and diseases, human mucosal layers have evolved to produce protective molecules, accommodate good microbes and keep the bad ones out of the blood stream
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