DNA methylation and mental retardation

Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation
Nan et al. (2007)
Proc Natl Acad Sci U S A 104: 2709–2714
Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMTL (ADD) domain of the chromatin-associated protein ATRX
Argentaro et al. (2007)
Proc Natl Acad Sci U S A 104: 11939–11944     

Algorithms for sleep–wake identification using actigraphy: a comparative study and new results

The aim of this study was to investigate two new scoring algorithms employing artificial neural networks and decision trees for distinguishing sleep and wake states in infants using actigraphy and to validate and compare the performance of the proposed algorithms with known actigraphy scoring algorithms. The study employed previously recorded longitudinal physiological infant data set from the Collaborative Home Infant Monitoring Evaluation (CHIME) study conducted between 1994 and 1998 [ http://dccwww.bumc.bu.edu/ChimeNisp/Main_Chime.asp ; Sleep 26 (1997) 553 ] at five clinical sites around the USA. The original CHIME data set contains recordings of 1079 infants <1 year old. In our study, we used the overnight polysomnography scored data and ankle actimeter (Alice 3) raw data for 354 infants from this data set. The participants were heterogeneous and grouped into four categories: healthy term, preterm, siblings of SIDS and infants with apparent life‐threatening events (apnea of infancy). The selection of the most discriminant actigraphy features was carried out using Fisher’s discriminant analysis. Approximately 80% of all the epochs were used to train the artificial neural network and decision tree models. The models were then validated on the remaining 20% of the epochs. The use of artificial neural networks and decision trees was able to capture potentially nonlinear classification characteristics, when compared to the previously reported linear combination methods and hence showed improved performance. The quality of sleep–wake scoring was further improved by including more wake epochs in the training phase and by employing rescoring rules to remove artifacts. The large size of the database (approximately 337 000 epochs for 354 patients) provided a solid basis for determining the efficacy of actigraphy in sleep scoring. The study also suggested that artificial neural networks and decision trees could be much more routinely utilized in the context of clinical sleep search.     

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.