Changepoint detection in base-resolution methylome data reveals a robust signature of methylated domain landscape.

BACKGROUND: Base-resolution methylome data generated by whole-genome bisulfite sequencing (WGBS) is often used to segment the genome into domains with distinct methylation levels. However, most segmentation methods include many parameters to be carefully tuned and/or fail to exploit the unsurpassed resolution of the data. Furthermore, there is no simple method that displays the composition of the domains to grasp global trends in each methylome. RESULTS: We propose to use changepoint detection for domain demarcation based on base-resolution methylome data. While the proposed method segments the methylome in a largely comparable manner to conventional approaches, it has only a single parameter to be tuned. Furthermore, it fully exploits the base-resolution of the data to enable simultaneous detection of methylation changes in even contrasting size ranges, such as focal hypermethylation and global hypomethylation in cancer methylomes. We also propose a simple plot termed methylated domain landscape (MDL) that globally displays the size, the methylation level and the number of the domains thus defined, thereby enabling one to intuitively grasp trends in each methylome. Since the pattern of MDL often reflects cell lineages and is largely unaffected by data size, it can serve as a novel signature of methylome. CONCLUSIONS: Changepoint detection in base-resolution methylome data followed by MDL plotting provides a novel method for methylome characterization and will facilitate global comparison among various WGBS data differing in size and even species origin.

Polymorphisms of the factor VII gene associated with the low activities of vitamin K-dependent coagulation factors in one-month-old infants.

Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.

Relationship between human cytomegalovirus glycoprotein B genotype and serum alanine aminotransferase elevation in infants.

The glycoprotein B (gB) region of the human cytomegalovirus (HCMV) is a major envelope glycoprotein that is a principal target of neutralizing antibodies and is known to stimulate the immune response of cytotoxic T lymphocytes. HCMV is currently classified into four genotypes on the basis of the nucleotide sequence of the gB region. The presence of HCMV in patients under 3 years of age was determined by subjecting urine samples taken from the patients to polymerase chain reaction (PCR) analysis. Analysis by direct sequencing of the gB region was carried out in 90 cases. These cases were grouped into the gB genotype 1 and gB genotype 3. Of 28 cases with a peak serum alanine aminotransferase (ALT) level(> or =100 IU/l), the duration of observed serum ALT elevation in the gB genotype 1 patients (166.7+/-126.7 days [mean+/-S.D.] [19 cases]) was significantly longer than that in the gB genotype 3 patients (39.7+/-31.7 days [9 cases]) (p<0.01). In the 54 cases with a serum ALT level(> or =50 IU/l), similar tendency was seen (p<0.05). These findings suggest that when serum ALT elevation is confirmed in young children infected with HCMV, analysis of the gB region is helpful for prediction of the duration of serum ALT elevation in the early stage of infection.