Biomedical subjects

Vardhman K Rakyan

Publications and source records attributed to Vardhman K Rakyan.

7 recordsLinked to original sources

PubMed2024

Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank.

The phenotypic impact of genetic variation of repetitive features in the human genome is currently understudied. One such feature is the multi-copy 47S ribosomal DNA (rDNA) that codes for rRNA components of the ribosome. Here, we present an analysis of rDNA copy number (CN) variation in the UK Biobank (UKB). From the first release of UKB whole-genome sequencing (WGS) data, a discovery analysis in White British individuals reveals that rDNA CN associates with altered counts of specific blood cell subtypes, such as neutrophils, and with the estimated glomerular filtration rate, a marker of kidney function. Similar trends are observed in other ancestries. A range of analyses argue against reverse causality or common confounder effects, and all core results replicate in the second UKB WGS release. Our work demonstrates that rDNA CN is a genetic influence on trait variance in humans.

Humans↗

PubMed2006

DNA methylation profiling of human chromosomes 6, 20 and 22.

DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5' UTRs and that about one-third of the differentially methylated 5' UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

5' Untranslated Regions↗

PubMed2006

Epigenetic variation and inheritance in mammals.

What determines phenotype is one of the most fundamental questions in biology. Historically, the search for answers had focused on genetic or environmental variants, but recent studies in epigenetics have revealed a third mechanism that can influence phenotypic outcomes, even in the absence of genetic or environmental heterogeneity. Even more surprisingly, some epigenetic variants, or epialleles, can be inherited by the offspring, indicating the existence of a mechanism for biological heredity that is not based on DNA sequence. Recent work from mouse models, human monozygotic twin studies, and large-scale epigenetic profiling suggests that epigenetically determined phenotypes and epigenetic inheritance are more common than previously appreciated.

Animals↗

PubMed2005

From genome to epigenome.

The success of the human genome sequencing project has created wide-spread interest in exploring the human epigenome in order to elucidate how the genome executes the information it holds. Although all (nucleated) human cells effectively contain the same genome, they contain very different epigenomes depending upon cell type, developmental stage, sex, age and various other parameters. This complexity makes it intrinsically difficult to precisely define 'an' epigenome, let alone 'the' epigenome. What is clear, however, is that in order to unravel any epigenome, existing and novel high-throughput approaches on the DNA, RNA and protein levels need to be harnessed and integrated. Here, we review the current thinking and progress on how to get from the genome to the epigenome(s) and discuss some potential applications.

Base Sequence↗

PubMed2004

DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.

The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine-guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data.

CpG Islands↗

PubMed2003

Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission.

Phenotypic variation that cannot be explained by genetic or environmental heterogeneity has intrigued geneticists for decades. The molecular basis of this phenomenon, however, is largely a mystery. Axin-fused (Axin(Fu)), first identified in 1937, is a classic example of a mammalian allele displaying extremely variable expression states. Here we demonstrate that the presence or absence of its characteristic phenotype, a kinked tail, correlates with differential DNA methylation at a retrotransposon within Axin(Fu) and identify mutant transcripts arising adjacent to the retrotransposon LTR that are likely to be causative of the phenotype. Furthermore, the epigenetic state at Axin(Fu) can be inherited transgenerationally after both maternal and paternal transmission. This is in contrast to epigenetic inheritance at the murine agouti-viable yellow (A(vy)) allele, which occurs through the female only. Unlike the egg, the sperm contributes very little (if any) cytoplasm to the zygote, and therefore paternal inheritance at Axin(Fu) argues against the possibility that the effects are due to cytoplasmic or metabolic influences. Consistent with the idea of transgenerational inheritance of epigenetic marks, we find that the methylation state of Axin(Fu) in mature sperm reflects the methylation state of the allele in the somatic tissue of the animal, suggesting that it does not undergo epigenetic reprogramming during gametogenesis. Finally, we show that epigenetic inheritance is influenced by strain background. These findings enable us to propose a model for transgenerational epigenetic inheritance in mammals.

Alleles↗

PubMed2002

Metastable epialleles in mammals.

There are some mammalian alleles that display the unusual characteristic of variable expressivity in the absence of genetic heterogeneity. It has recently become evident that this is because the activity of these alleles is dependent on their epigenetic state. Interestingly, the epigenetic state is somewhat labile, resulting in phenotypic mosaicism between cells (variegation) and also between individuals (variable expressivity). The establishment of the epigenetic state occurs during early embryogenesis and is a probabilistic event that is influenced by whether the allele is carried on the paternal or maternal alleles. In addition, the epigenetic state determines whether these alleles are dominant. We propose that mammalian alleles with such characteristics should be termed metastable epialleles to distinguish them from traditional alleles. At this stage, it is unclear how common these alleles are, but an appreciation of their existence will aid in their identification.

Alleles↗