Wendy P. Robinson

Bio: Wendy P. Robinson is an academic researcher from University of British Columbia. The author has contributed to research in topics: DNA methylation & Trisomy. The author has an hindex of 61, co-authored 244 publications receiving 12023 citations. Previous affiliations of Wendy P. Robinson include The Centre for Applied Genomics & University of Zurich.

Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array

Abstract: Background Measurement of genome-wide DNA methylation (DNAm) has become an important avenue for investigating potential physiologically-relevant epigenetic changes. Illumina Infinium (Illumina, San Diego, CA, USA) is a commercially available microarray suite used to measure DNAm at many sites throughout the genome. However, it has been suggested that a subset of array probes may give misleading results due to issues related to probe design. To facilitate biologically significant data interpretation, we set out to enhance probe annotation of the newest Infinium array, the HumanMethylation450 BeadChip (450 k), with >485,000 probes covering 99% of Reference Sequence (RefSeq) genes (National Center for Biotechnology Information (NCBI), Bethesda, MD, USA). Annotation that was added or expanded on includes: 1) documented SNPs in the probe target, 2) probe binding specificity, 3) CpG classification of target sites and 4) gene feature classification of target sites. Results Probes with documented SNPs at the target CpG (4.3% of probes) were associated with increased within-tissue variation in DNAm. An example of a probe with a SNP at the target CpG demonstrated how sample genotype can confound the measurement of DNAm. Additionally, 8.6% of probes mapped to multiple locations in silico . Measurements from these non-specific probes likely represent a combination of DNAm from multiple genomic sites. The expanded biological annotation demonstrated that based on DNAm, grouping probes by an alternative high-density and intermediate-density CpG island classification provided a distinctive pattern of DNAm. Finally, variable enrichment for differentially methylated probes was noted across CpG classes and gene feature groups, dependant on the tissues that were compared. Conclusion DNAm arrays offer a high-throughput approach for which careful consideration of probe content should be utilized to better understand the biological processes affected. Probes containing SNPs and non-specific probes may affect the assessment of DNAm using the 450 k array. Additionally, probe classification by CpG enrichment classes and to a lesser extent gene feature groups resulted in distinct patterns of DNAm. Thus, we recommend that compromised probes be removed from analyses and that the genomic context of DNAm is considered in studies deciphering the biological meaning of Illumina 450 k array data.

Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case–control study

Abstract: BACKGROUND: Reproductive loss carries immeasurable human costs as well as being costly to the health care system. The objectives of this study were to determine the frequency and distribution of cytogenetically abnormal miscarriages from couples with recurrent miscarriage and to compare the results with the general population. METHODS: A total of 420 specimens, including 29 pre-clinical, 237 embryonic and 154 fetal, were successfully karyotyped from 285 couples with recurrent miscarriage. The results were stratified according to maternal age and compared with controls. RESULTS: In all, 225 specimens (54%) were euploid. A total of 195 specimens (46%) were cytogenetically abnormal, of which 131 (66.5%) were trisomic, 37 (19%) were polyploid, 18 (9%) were monosomy X, eight (4%) were unbalanced translocations and one was a combination of trisomy 21 and monosomy X. The frequency of euploid miscarriages was significantly higher in women <36 years of age with recurrent miscarriage compared with controls. The distribution of cytogenetic abnormalities in the recurrent miscarriage group was not significantly different from controls, when stratified by maternal age. CONCLUSIONS: Women <36 years of age with recurrent miscarriage have a higher frequency of euploid miscarriage. When stratified for maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with recurrent miscarriage compared with controls.

Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of caucasians with insulin-dependent diabetes mellitus

Abstract: From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a "recessive"-like and DR4 in a "dominant"-like or "intermediate" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.

Mechanisms leading to uniparental disomy and their clinical consequences.

Abstract: Uniparental disomy (UPD) refers to the situation in which both copies of a chromosome pair have originated from one parent In humans, it can result in clinical conditions by producing either homozygosity for recessive mutations or aberrant patterns of imprinting Furthermore, UPD is frequently found in conjunction with mosaicism for a chromosomally abnormal cell line, which can also contribute to phenotypic abnormalities Investigations into the mechanisms by which UPD may arise have helped to expand our general awareness of the impact of chromosomal abnormalities and chromosomal mosaicism in normal human development Specifically, it appears that errors in the transmission of a chromosome from parent to gamete and during early somatic cell divisions are remarkably common but that embryo and cell selection during early embryogenesis help to ensure the presence of a numerically balanced chromosome complement in the developing fetus UPD is also likely to occur within a portion of cells in all individuals simply as a consequence of somatic recombination occurring during mitotic cell divisions This can be an important step in cancer development as well as a contributing factor to other late onset diseases This review summarizes mechanisms by which UPD may arise and their associated clinical consequences BioEssays 22:452—459, 2000 © 2000 John Wiley & Sons, Inc

Uniparental disomy 7 in Silver—Russell syndrome and primordial growth retardation

Abstract: Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardation.

DNA methylation age of human tissues and cell types

Abstract: It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).

Abstract: A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.

Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA Methylation microarrays

Abstract: Motivation The recently released Infinium HumanMethylation450 array (the '450k' array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ∼450 000 loci across a range of genomic features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost-effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years. Results Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods. Availability and implementation http://bioconductor.org/packages/release/bioc/html/minfi.html. Contact khansen@jhsph.edu; rafa@jimmy.harvard.edu Supplementary information Supplementary data are available at Bioinformatics online.

Genomic imprinting: parental influence on the genome

Abstract: Genomic imprinting affects several dozen mammalian genes and results in the expression of those genes from only one of the two parental chromosomes. This is brought about by epigenetic instructions--imprints--that are laid down in the parental germ cells. Imprinting is a particularly important genetic mechanism in mammals, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother. Consistent with this view is the fact that imprinted genes tend to affect growth in the womb and behaviour after birth. Aberrant imprinting disturbs development and is the cause of various disease syndromes. The study of imprinting also provides new insights into epigenetic gene modification during development.

To err (meiotically) is human: the genesis of human aneuploidy

Abstract: Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.