Posts tagged human genome
Articles and news from the latest research reports.
DNA methylation involved in Alzheimer’s disease
A new study led by researchers at Brigham and Women’s Hospital (BWH) and Rush University Medical Center, reveals how early changes in brain DNA methylation are involved in Alzheimer’s disease. DNA methylation is a biochemical alteration of the building blocks of DNA and is one of the markers that indicate whether the DNA is open and biologically active in a given region of the human genome.
The study is published online August 17, 2014 in Nature Neuroscience.
According to the researchers, this is the first large-scale study employing epigenome-wide association (EWAS) studies—which look at chromosomal make-up and changes—in relation to the brain and Alzheimer’s disease.
"Our study approach may help us to better understand the biological impact of environmental risk factors and life experiences on Alzheimer’s disease," said Philip L. De Jager, MD, PhD, Program in Translational Neuropsychiatric Genomics, BWH Departments of Neurology and Psychiatry, lead study author. "There are certain advantages to studying the epigenome, or the chemical changes that occur in DNA. The epigenome is malleable and may harbor traces of life events that influence disease susceptibility, such as smoking, depression and menopause, which may influence susceptibility to Alzheimer’s and other diseases."
The researchers analyzed samples from 708 donated brains from subjects in the Religious Orders Study and Rush Memory and Aging Project, conducted by study co-author, David A. Bennett, MD, Rush Alzheimer’s Disease Center in Chicago. They found that methylation levels correlated with Alzheimer’s disease in 71 of 415,848 CpG markers analyzed (these are a pair of DNA building blocks consisting of a cytosine and a guanine nucleotide that are located next to each other). These 71 markers were found in the ANK1 and RHBDF2 genes, as well as ABCA7 and BIN1 which harbor known Alzheimer’s disease susceptibility variants.
Further, investigation of these CpG associations revealed nearby genes whose RNA expression was altered in brain samples with Alzheimer’s disease: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This suggests that the CpG associations identify genes whose function is altered in Alzheimer’s disease.
Further, “because these findings are also found in the subset of subjects that are not cognitively impaired at the time of death, it appears that these DNA methylation changes may play a role in the onset of Alzheimer’s disease,” said De Jager. “Moreover, our work has helped identify regions of the human genome that are altered over the life-course in a way that is associated with Alzheimer’s disease. This may provide clues to treating the disease by using drugs that influence epigenomic function.”
(Source: eurekalert.org)
New insight into the human genome through the lens of evolution
By comparing the human genome to the genomes of 34 other mammals, Australian scientists have described an unexpectedly high proportion of functional elements conserved through evolution.
Less than 1.5% of the human genome is devoted to conventional genes, that is, encodes for proteins. The rest has been considered to be largely junk. However, while other studies have shown that around 5-8% of the genome is conserved at the level of DNA sequence, indicating that it is functional, the new study shows that in addition much more, possibly up to 30%, is also conserved at the level of RNA structure.
DNA is a biological blueprint that must be copied into another form before it can be actualised. Through a process known as ‘transcription’, DNA is copied into RNA, some of which ‘encodes’ the proteins that carry out the biological tasks within our cells. Most RNA molecules do not code for protein, but instead perform regulatory functions, such as determining the ways in which genes are expressed.
Like infinitesimally small Lego blocks, the nucleic acids that make up RNA connect to each other in very specific ways, which force RNA molecules to twist and loop into a variety of complicated 3D structures.
Dr Martin Smith and Professor John Mattick, from Sydney’s Garvan Institute of Medical Research, devised a method for predicting these complex RNA structures – more accurate than those used in the past – and applied it to the genomes of 35 different mammals, including bats, mice, pigs, cows, dolphins and humans. At the same time, they matched mutations found in the genomes with consistent RNA structures, inferring conserved function. Their findings are published in Nucleic Acids Research, now online.
“Genomes accumulate mutations over time, some of which don’t change the structure of associated RNAs. If the sequence changes during evolution, yet the RNA structure stays the same, then the principles of natural selection suggest that the structure is functional and is required for the organism,” explained Dr Martin Smith.
“Our hypothesis is that structures conserved in RNA are like a common template for regulating gene expression in mammals – and that this could even be extrapolated to vertebrates and less complex organisms.”
“We believe that RNA structures probably operate in a similar way to proteins, which are composed of structural domains that assemble together to give the protein a function.”
“We suspect that many RNA structures recruit specific molecules, such as proteins or other RNAs, helping these recruited elements to bond with each other. That’s the general hypothesis at the moment – that non-coding RNAs serve as scaffolds, tethering various complexes together, especially those that control genome organization and expression during development.”
“We know that many RNA transcripts are associated with diseases and developmental conditions, and that they are differentially expressed in distinct cells.”
“Our structural predictions can serve as an annotative tool to help researchers understand the function of these RNA transcripts.”
“That is the first step – the next is to describe the structures in more detail, figure out exactly what they do in the cell, then work out how they relate to our normal development and to disease.”
(Source: garvan.org.au)
It’s All About the Genes and the Brain Machines
(Image: U.S. Dept. of Energy Office of Science)
The amount of time and money needed to sequence genomes continued to fall this year, perhaps to no one’s surprise. But while the field seemed to be finally approaching the heralded $1,000 human genome, the implications of reaching that milestone are not clear. Without expert analysis, the result of sequencing a human genome is just a large file of letters. You still need to manipulate and understand what those letters mean. Different companies announced services to help, from initial processing and storage of data to interpretation of the genetic data into medical meaning.
As human genomics garnered more attention from the medical community, the technology attracted new business opportunities. In April, the company behind the most widely used DNA sequencer, Illumina, fought off a hostile bid from pharmaceutical giant Roche. Just seven months later, Illumina tried to take over Complete Genomics, a company with technology well suited to medical genomics but which has never achieved financial success. That offer followed what seemed to be an all-but-assured purchased of Complete Genomics by China’s BGI. Illumina and BGI continue to fight over Complete Genomics.
Still, the medical community is only at the cusp of its understanding of how genome sequences can be used to help patients. Two branches of medicine that seem to be at the forefront of bringing on board DNA technology are reproductive medicine and cancer. Early in the summer, scientists at the University of Washington in Seattle reported a technique for determining the genome sequence of a fetus by analyzing DNA in the mother’s blood and from the father. Illumina’s CEO Jay Flatley said that prenatal diagnostics will be a major focus for the company, which has been expanding its business from sequencer manufacturing to broad DNA analysis service. In September, Illumina purchased BlueGnome, a chromosome-focused diagnostic company whose technology can detect abnormal numbers of chromosomes in IVF embryos. DNA analysis could also help prior to conception, according to a start-up called GenePeeks. That company announced it would offer predictive genome analysis for sperm bank clients to help guide them away from risky donor matches.
Cancer patients and their doctors were also early adopters of medical genome science this year. Cancer is a disease of the genome: genetic mutations lead to abnormal cellular proliferation and behavior. Each person’s tumor and even different cells within a single tumor can have a unique profile of mutations, which makes finding the right drug to treat each patient difficult. Cambridge, Massachusetts-based Foundation Medicine offered a sequencing service that searches for mutations that can be addressed with drugs in a patient’s tumor. Another Cambridge company, H3 Biomedicine, is using public databases of tumor sequences to find new drug targets specific to certain patient populations.
Genetic medicines also got a boost with the first Western approval of gene therapy in November. Amsterdam-based Uniqure will begin selling its virus-mediated gene correction for a rare metabolic disorder sometime next year. The announcement could be good news for other companies trying to develop gene therapies as well as other groups developing molecular medicines, such as gene-silencing RNAi treatments that continue to move through clinical trials.
Although still untested in patients, another genetic manipulation is proving to be a powerful tool for neuroscientists. With optogenetics, scientists can manipulate neuron activity with flashes of light, and this year a group demonstrated for the first time that primate behavior could be controlled with the technique. Lab animal studies this year suggest optogenetics might one day help patients with blindness caused by retinal degeneration.
The melding of mind and machine was also big this year. Scientists in Winston-Salem, North Carolina, demonstrated that a brain implant could replace some cognitive function in primates, which could one day help people with brain damage. On the flip side, two research groups published the first accounts of quadriplegic people using brain implants to control robotic limbs. The implants recorded the participants’ intentions to move, which were translated by a computer into instructions for a robotic arm. The idea is that one day people with severe paralysis or amputations could use such neural prosthetics at home to help with the tasks of daily life.
Brain electronics were also implanted into Alzheimer’s patients this year in an attempt to slow a disease that has so far evaded pharmaceutical treatment. The urgency for treatment is growing, but the community still doesn’t know what sets into motion the cascade of molecular events that robs people of their memory and thinking skills. With better diagnostic tools and the discovery that there are warnings decades before symptoms, scientists are turning to treating patients with a genetic predisposition for the disease before they start having symptoms. Perhaps this will be the key to treatments in future years.
(Source: technologyreview.com)
![According to ENCODE’s analysis, 80 percent of the genome has a “biochemical function”. More on exactly what this means later, but the key point is: It’s not “junk”.
Scientists have long recognised that some non-coding DNA has a function, and more and more solid examples have come to light [edited for clarity - Ed]. But, many maintained that much of these sequences were, indeed, junk. ENCODE says otherwise. “Almost every nucleotide is associated with a function of some sort or another, and we now know where they are, what binds to them, what their associations are, and more,” says Tom Gingeras, one of the study’s many senior scientists.
And what’s in the remaining 20 percent? Possibly not junk either, according to Ewan Birney, the project’s Lead Analysis Coordinator and self-described “cat-herder-in-chief”. He explains that ENCODE only (!) looked at 147 types of cells, and the human body has a few thousand. A given part of the genome might control a gene in one cell type, but not others. If every cell is included, functions may emerge for the phantom proportion. “It’s likely that 80 percent will go to 100 percent,” says Birney. “We don’t really have any large chunks of redundant DNA. This metaphor of junk isn’t that useful.”
That the genome is complex will come as no surprise to scientists, but ENCODE does two fresh things: it catalogues the DNA elements for scientists to pore over; and it reveals just how many there are. “The genome is no longer an empty vastness – it is densely packed with peaks and wiggles of biochemical activity,” says Shyam Prabhakar from the Genome Institute of Singapore. “There are nuggets for everyone here. No matter which piece of the genome we happen to be studying in any particular project, we will benefit from looking up the corresponding ENCODE tracks.”](http://41.media.tumblr.com/tumblr_m9y0xaewSN1rog5d1o1_500.jpg)
According to ENCODE’s analysis, 80 percent of the genome has a “biochemical function”. More on exactly what this means later, but the key point is: It’s not “junk”.
Scientists have long recognised that some non-coding DNA has a function, and more and more solid examples have come to light [edited for clarity - Ed]. But, many maintained that much of these sequences were, indeed, junk. ENCODE says otherwise. “Almost every nucleotide is associated with a function of some sort or another, and we now know where they are, what binds to them, what their associations are, and more,” says Tom Gingeras, one of the study’s many senior scientists.
And what’s in the remaining 20 percent? Possibly not junk either, according to Ewan Birney, the project’s Lead Analysis Coordinator and self-described “cat-herder-in-chief”. He explains that ENCODE only (!) looked at 147 types of cells, and the human body has a few thousand. A given part of the genome might control a gene in one cell type, but not others. If every cell is included, functions may emerge for the phantom proportion. “It’s likely that 80 percent will go to 100 percent,” says Birney. “We don’t really have any large chunks of redundant DNA. This metaphor of junk isn’t that useful.”
That the genome is complex will come as no surprise to scientists, but ENCODE does two fresh things: it catalogues the DNA elements for scientists to pore over; and it reveals just how many there are. “The genome is no longer an empty vastness – it is densely packed with peaks and wiggles of biochemical activity,” says Shyam Prabhakar from the Genome Institute of Singapore. “There are nuggets for everyone here. No matter which piece of the genome we happen to be studying in any particular project, we will benefit from looking up the corresponding ENCODE tracks.”
What Is the Human Genome?
The human genome that researchers sequenced at the turn of the century doesn’t really exist as we know it.
The Human Genome project sequenced “the human genome” and is widely credited with setting in motion the most exciting era of fundamental new scientific discovery since Galileo. That’s remarkable, because in important ways “the human genome” that we have labeled as such doesn’t actually exist.
cosmin4000, istockphoto
Plato essentially asserted that things like chairs and dogs, which we observe in this physical world, and even concepts like virtues, are but imperfect representations or instances of some ideal that exists, but not in the material world. Such a Platonic ideal is “the human genome,” a sequence of about 3 billion nucleotides arrayed across a linear scale of position from the start of chromosome 1 to the end of the sex chromosomes. Whether it was obtained from one person or several has so far been shrouded in secrecy for bioethical reasons, but it makes no real difference. What we call the human genome sequence is really just a reference: it cannot account for all the variability that exists in the species, just like no single dog on earth, real or imagined, can fully incorporate all the variability in the characteristics of dogs.
Nor is the human genome we have a “’normal” genome. What would it mean to be “normal” for the nucleotide at position 1,234,547 on chromosome 11? All we know is that the donor(s) had no identified disease when bled for the cause, but sooner or later some disease will arise. Essentially all available whole genome sequences show potentially disease-producing variants, even including nonfunctional genes, in donors who were unaffected at the time.
