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Browsing by Author "Silva, Ana M."

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  • Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells
    Publication . Silva, Ana M.; Brown, Jill M.; Buckle, Veronica J.; Wade-Martins, Richard; Lufino, Michele M. P.
    Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single-cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur.
    2015Journal article Restricted access Show more
  • The population genomics of archaeological transition in west Iberia: Investigation of ancient substructure using imputation and haplotype-based methods
    Publication . Martiniano, Rui; Cassidy, Lara M.; Ó'Maoldúin, Ros; McLaughlin, Russell; Silva, Nuno M.; Manco, Licinio; Fidalgo, Daniel; Pereira, Tania; Coelho, Maria J.; Serra, Miguel; Burger, Joachim; Parreira, Rui; Moran, Elena; Valera, Antonio C.; Porfirio, Eduardo; Boaventura, Rui; Silva, Ana M.; Bradley, Daniel G.
    We analyse new genomic data (0.05-2.95x) from 14 ancient individuals from Portugal distributed from the Middle Neolithic (4200-3500 BC) to the Middle Bronze Age (1740-1430 BC) and impute genomewide diploid genotypes in these together with published ancient Eurasians. While discontinuity is evident in the transition to agriculture across the region, sensitive haplotype-based analyses suggest a significant degree of local hunter-gatherer contribution to later Iberian Neolithic populations. A more subtle genetic influx is also apparent in the Bronze Age, detectable from analyses including haplotype sharing with both ancient and modern genomes, D-statistics and Y-chromosome lineages. However, the limited nature of this introgression contrasts with the major Steppe migration turnovers within third Millennium northern Europe and echoes the survival of non-Indo-European language in Iberia. Changes in genomic estimates of individual height across Europe are also associated with these major cultural transitions, and ancestral components continue to correlate with modern differences in stature.
    2017Journal article Open access Show more