A newborn’s blood spotted onto a Guthrie card. Photo: The New York State Department of Health Newborn Screening Program.

Over the last 50 years, the spotting of newborn’s blood onto filter paper for disease screening, called Guthrie cards, has become so routine that since 2000, more than 90% of newborns in the United States have had Guthrie cards created.  In a study published online in Genome Research (, researchers have shown that epigenetic information stored on archived Guthrie cards provides a retrospective view of the epigenome at birth, a powerful new application for the card that could help understand disease and predict future health.

DNA methylation, an epigenetic chemical modification of DNA, is known to affect gene activity and play a role in normal development, aging, and also in diseases such as heart disease, diabetes, and cancer.  “But are these epigenetic marks involved in causing the disease, or a result of the disease itself?” asked Dr. Vardhman Rakyan of Queen Mary, University of London and co-senior author of the study.  Rakyan explained that this is impossible to know when samples are obtained after onset of the disease.  Guthrie cards, commonly used to collect blood spots from the pricked heel of newborns to screen for diseases such as phenylketonuria, cystic fibrosis, and sickle cells disorders, might offer a snapshot of the epigenome before disease develops.  Many Guthrie cards are stored indefinitely by health authorities around the world, posing a potential wealth of information about the epigenome at birth.

Rakyan and an international group of colleagues purified genomic DNA and analyzed DNA methylomes from Guthrie cards and verified that this archived DNA yields high-quality methylation data when compared to fresh samples.  The researchers then compared the DNA methylation profiles of newborns to the same healthy individuals at the age of three, looking for epigenetic variations detected in the Guthrie card sample that are stable into the early years of life.

“We found similar epigenetic differences between different people both at birth and when they were three years old,” said Rakyan, who added that these differences, already present at birth, are unlikely due solely to inherent genetic differences between the individuals, but also due to environment or random events in utero.  Furthermore, Guthrie card samples could be analyzed for both genetic and epigenetic differences together to view a more complete picture of the genome at birth.

Guthrie card methylomics is a potentially powerful new application for archived blood spots, which could provide a wealth of information about epigenetics and disease, and could give clues about health later in life.  Dr. David Leslie, co-senior author of the study, added that because national health authorities routinely make Guthrie cards available, and with the proper consent obtained from parents and children, “we are talking about an invaluable, and non-renewable, resource for millions of individuals.”

Your genes determine much about you, but environment can have a strong influence on your genes even before birth, with consequences that can last a lifetime.  In a study published online in Genome Research (, researchers have for the first time shown that the environment experienced in the womb defines the newborn epigenetic profile, the chemical modifications to DNA we are born with, that could have implications for disease risk later in life.

Epigenetic tagging of genes by a chemical modification called DNA methylation is known to affect gene activity, playing a role in normal development, aging, and also in diseases such as diabetes, heart disease, and cancer.  Studies conducted in animals have shown that the environment shapes the epigenetic profile across the genome, called the epigenome, particularly in the womb.  An understanding of how the intrauterine environment molds the human epigenome could provide critical information about disease risk to help manage health throughout life.

Twin pairs, both monozygotic (identical) and dizygotic (fraternal), are ideal for epigenetic study because they share the same mother but have their own umbilical cord and amniotic sac, and in the case of identical twins, also share the same genetic make-up.  Previous studies have shown that methylation can vary significantly at a single gene across multiple tissues of identical twins, but it is important to know what the DNA methylation landscape looks like across the genome.

In this report, an international team of researchers has for the first time analyzed genome-scale DNA methylation profiles of umbilical cord tissue, cord blood, and placenta of newborn identical and fraternal twin pairs to estimate how genes, the shared environment that their mother provides and the potentially different intrauterine environments experienced by each twin contribute to the epigenome.  The group found that even in identical twins, there are widespread differences in the epigenetic profile of twins at birth.

“This must be due to events that happened to one twin and not the other,” said Dr. Jeffrey Craig of the Murdoch Childrens Research Institute (MCRI) in Australia and a senior author of the report.  Craig added that although twins share a womb, the influence of specific tissues like the placenta and umbilical cord can be different for each fetus, and likely affects the epigenetic profile.

Interestingly, the team found that methylated genes closely associated with birth weight in their cohort are genes known to play roles in growth, metabolism, and cardiovascular disease, lending further support to a known link between low birth weight and risk for diseases such as diabetes and heart disease.  The authors explained that their findings suggest the unique environmental experiences in the womb may have a more profound effect on epigenetic factors that influence health throughout life than previously thought.

Furthermore, an understanding of the epigenetic profile at birth could be a particularly powerful tool for managing future health.  “This has potential to identify and track disease risk early in life, said Dr. Richard Saffery of the MCRI and a co-senior author of the study, “or even to modify risk through specific environmental or dietary interventions.”

The human gut is home to a teeming ecosystem of microbes that is intimately involved in both human health and disease.  But while the gut microbiota is interacting with our body, they are also under constant attack from viruses.  In a study published online in Genome Research, researchers have analyzed a bacterial immune system, revealing a common set of viruses associated with gut microbiota in global populations.

Viruses that prey on bacteria, called phages, pose a constant threat to the health of bacterial communities.  In many ecological systems, viruses outnumber bacterial cells ten to one.  Given the richness of bacteria in the human gut, it was not surprising that scientists have found that phages are also highly prevalent.  But how can viruses targeting gut microbiota be identified?  How do viral communities differ between people and global populations, and what could this tell us about human health and disease?

In this report, a team of scientists from Israel has taken advantage of information coded in a bacterial immune system to shed new light on these questions.  Bacteria can “steal” small pieces of DNA from phages that attack them, and use these stolen pieces to recognize and respond to the attacker, in a manner similar to usage of antibodies by the human immune system. The stolen DNA pieces are stored in specific places in the bacterial genome called CRISPR loci (clustered regularly interspaced short palindromic repeats).

“In our study we searched for such stolen phage DNA pieces carried by bacteria living in the human gut,” said Rotem Sorek of the Weizmann Institute of Science and senior author of the study.  “We then used these pieces to identify DNA of phages that co-exist with the bacteria in the gut.”

Sorek’s team used this strategy to identify and analyze phages present in the gut microbiota of a cohort of European individuals.  They found that nearly 80% of the phages are shared between two or more individuals.  The team compared their data to samples previously derived from American and Japanese individuals, finding phages from their European data set also present in these geographically distant populations, a surprising result given the diversity of phages seen in other ecological niches.

Sorek explained that their findings mean that there are hundreds of types of viruses that repeatedly infect our gut microbiota.  “These viruses can kill some of our gut bacteria,” said Sorek. “It is therefore likely that these viruses can influence human health.”

The authors note that as evidence for the beneficial roles played by bacteria in the healthy human gut continues to mount, it is critical that we understand the pressures placed upon the “good” bacteria that are vital to human health.  “Our discovery of a large set of phages attacking these good bacteria in our gut opens a window for understanding how they affect human health,” Sorek added.  Researchers can now begin to ask how phage dynamics in the gut changes over time, and what it might tell us about diseases, such as inflammatory bowel disease, and how to more effectively treat them.

Mutation: The History of an Idea from Darwin to GenomicsMutations are central to biology—they explain diversity in life forms, provide fuel for evolution, and determine one’s susceptibility to certain diseases.  But scientists have not always understood mutations as we do now—as molecular alterations in DNA.

“Mutation, of course, involves change,” writes Elof Axel Carlson. “But our understanding of that change is influenced by the time we live in.”  In his latest book, Carlson explores the history—the people, science, and ideas—behind the concept of mutation.

Carlson describes how the idea of mutation has changed considerably from the pre-Mendelian concepts of Darwin’s generation over 150 years ago. Darwin viewed “fluctuating variations” as the raw material on which evolution acted. (more…)

Speaking of Genetics: A Collection of InterviewsSpeaking of Genetics, Jane Gitschier’s collection of interviews with prominent scientists and non-scientists involved in genetics, is reviewed in the current issue of CHOICE.  In the review, Randall Harris (William Carey University) says the interviews “give the reader the feeling of sitting in on an evening gathering among friends.”

Researchers convey the exhilarating moments of discovery, as well as the hard work, serendipity, joy, and frustration involved. Harris says the book “will prove inspirational to scientists at all stages of their careers.”

Guide to the Human GenomeThere’s much excitement here at CSHL in anticipation of the popular annual Biology of Genomes meeting, which begins tonight. For the next 6 days, scientists from around the world will assemble on campus to discuss the latest advances in genome research as they relate to evolution, biology, and disease in a variety of organisms—including humans.

This year marks the 10th anniversary of the publication of the draft human genome sequence. What has it told us about human biology? Do we know the function of every gene in the human genome?

To address these questions, Stewart Scherer has spent substantial time and effort compiling information from the scientific literature about human genes and their biological functions.  The result is a new online resource, Guide to the Human Genome, that puts the genes of the human genome in their biological context. The Guide, available at, provides extensive up-to-date information about human genes in an easily accessible format. (more…)

Cap analysis gene expression (CAGE) is a method used to discover new promoters and for quantifying gene activity, providing data essential for studies of regulatory gene networks. But CAGE requires large amounts of RNA, which are often not obtainable from rare specimens. In the January issue of Cold Spring Harbor Protocols Piero Carninci and colleagues from the RIKEN Yokohama Institute’s Omics Science Center present NanoCAGE: A High-Resolution Technique to Discover and Interrogate Cell Transcriptomes, a method that can capture information from as little as 10 nanograms of total RNA. The protocol describes how to rapidly prepare nanoCAGE libraries which can be sequenced with high sensitivity. As one of January’s featured articles, the protocol is freely available to subscribers and non-subscribers alike.

Blood feeding mosquitoes transmit many of the world’s deadliest diseases, which are resurgent in developing countries and pose threats for epidemic outbreaks in developed countries. Recent mosquito genome projects have stimulated interest in the potential for disease control through the genetic manipulation of vector insects. To accomplish this, vector insects must be established as laboratory model organisms, allowing for a better understanding of their biology, and in particular, the genes that regulate their development. Aedes aegypti is a vector mosquito of great medical importance because it is responsible for the transmission of dengue fever and yellow fever. In the October issue of Cold Spring Harbor Protocols, Molly Duman-Scheel and colleagues present an overview of the background, husbandry, and potential uses of Ae. aegypti as a model species. Protocols are provided for culturing and egg collection, fixation and tissue preparation, whole mount in situ hybridization, immunohistochemical analysis and RNA interference in Ae. aegypti. This methodology, much of which is applicable to other mosquito species, is useful to both the comparative development and vector research communities.

This article series marks the latest entrant in Cold Spring Harbor Protocols’ long-running series on Emerging Model Organisms.

Post-translational modifications of histones play an important role in regulating chromatin dynamics and function. One such modification, methylation, is involved in the regulation of the epigenetic program of a cell, determining chromatin structure, and regulating transcription. Methylation of histones occurs on both lysine and arginine residues, and until recently, was thought to be an irreversible process. The recent discovery of histone demethylases revealed that histone methylation is more dynamic than previously recognized. The October issue of Cold Spring Harbor Protocols features a set of methods from Keiichi Nakayama and colleagues from Kyushu University for investigating demethylase activity. The protocol, In Vitro Histone Demethylase Assay, describes two different in vitro histone demethylase enzyme reactions and three different methods for measuring histone demethylase activity. These methods can be applied to measuring histone demethylase activity in tissues and cell lysates, identification of novel histone demethylases, and screening for inhibitors of histone demethylases. As one of our featured articles, the protocol is freely available to subscribers and nonsubscribers alike.

A cell devotes a significant amount of effort to maintaining the stability of its genome, preventing the sorts of chromosomal rearrangements characteristic of many cancers. Assays that measure the rate of gross chromosomal rearrangements (GCRs) are needed in order to understand the individual genes and the different pathways that suppress genomic instability. In the September issue of Cold Spring Harbor Protocols, Richard Kolodner and colleagues from the University of California, San Diego’s Ludwig Institute for Cancer Research present Determination of Gross Chromosomal Rearrangement Rates, a genetic assay to quantitatively measure the rate at which GCRs occur in yeast cells. The assay measures the rate of simultaneous inactivation of two markers placed on a nonessential end of a yeast chromosome. This simple protocol for determining GCR mutation rates in a variety of genetic backgrounds coupled with a diversity of modified GCR assays has provided tremendous insight into the large numbers of pathways that suppress genomic instability in yeast and appear to be relevant to cancer suppression pathways in humans. As one of September’s featured articles, the full text protocol is freely available to subscribers and nonsubscribers alike.

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