̽��ֱ�� of Cambridge - Ernest Turro

Genomes front and centre of rare disease diagnosis

Anonymous — Wed, 24 Jun 2020 16:15:38 +0000

A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government to introduce routine genetic diagnostic testing in the NHS.

̽��ֱ��results of the study, published in the journal Nature, demonstrate that sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases. It was led by researchers at the ̽��ֱ�� of Cambridge together with Genomics England.

̽��ֱ��researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision.

̽��ֱ��programme offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. ̽��ֱ��integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months.

“Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed,” said Willem Ouwehand, Professor of Experimental Haematology at Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. “We felt it was vital to shorten this odyssey for patients and parents.

“This research shows that quicker and better genetic diagnosis will be possible for more NHS patients.”

In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

̽��ֱ��team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease – a few hundred ‘needles in the haystack’.

“Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care,” said Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London.

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

̽��ֱ��team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the ‘switches and dimmers’ of the genome – the regulatory elements in DNA that control the activity of the thousands of genes.

̽��ֱ��team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

“We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis,” said Dr Ernest Turro from the ̽��ֱ�� of Cambridge and the NIHR BioResource.

“Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases.”

Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource.

“In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield” said Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care.“This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. ̽��ֱ��sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the ‘standard of care’, ensuring equivalent care across the country.

̽��ֱ��benefits include a faster diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment.

Reference:
Turro E et al. ‘Whole-genome sequencing of patients with rare diseases in a national health system.’ Nature (2020). DOI: 10.1038/s41586-020-2434-2

Adapted from an NIHR press release.

Cambridge-led study discovers new genetic causes of rare diseases, potentially leading to improved diagnosis and better patient care.

This research shows that quicker and better genetic diagnosis will be possible for more NHS patients

Willem Ouwehand

National Human Genome Research Institute, National Institutes of Health

DNA Double Helix

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Interplay between mitochondria and the nucleus may have implications for changing cell’s ‘batteries’

cjb250 — Thu, 23 May 2019 18:00:47 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, suggests that matching mitochondrial DNA to nuclear DNA could be important when selecting potential donors for the recently-approved mitochondrial donation treatment, in order to prevent potential health problems later in life.

Almost all of the DNA that makes up the human genome – the body’s ‘blueprint’ – is contained within our cells’ nuclei. This is referred to as ‘nuclear DNA’. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as the ‘batteries’ that provide the energy for our cells to function. Each of these mitochondria is coded for by a tiny amount of ‘mitochondrial DNA’. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

Until now, scientists had thought that mitochondria were readily interchangeable, serving only to power our bodies, and so an individual’s mitochondria could be replaced with those from a donor with no consequences. However, in the first major population study to use data from the UK-wide 100,000 Genomes Project and its National Institute for Health Research (NIHR)-funded pilot project, researchers compared mitochondrial and nuclear DNA from tens of thousands of people and found that mitochondria may be fine-tuned to the nucleus.

̽��ֱ��researchers studied over 1,500 mother-child pairs and found that just under a half (45%) of individuals within these pairs harboured mutations affecting at least 1% of their mitochondrial DNA. Mutations in certain parts of mitochondrial DNA were more likely to be transmitted, such as those in the so-called D-loop region, which controls how mitochondrial DNA copies itself. Conversely, mutations in other parts of mitochondrial DNA were more likely to be suppressed, such as the code for how mitochondria produce their own proteins.

“Children inherit their DNA exclusively from their mother and we wanted to see how this explains the origins of mitochondrial diseases,” says first author Dr Wei Wei from the Medical Research Council (MRC) Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge. “What we found was that there is some kind of selection taking place when mitochondrial DNA is transmitted down a generation, allowing some mutations to be passed on and others to be blocked.”

Genetic variants that had previously been observed around the world were more likely to be passed on than completely new ones, the team found. This implies that there is a mechanism that filters the mitochondrial DNA when it is being passed down from mother to child, influencing the likelihood that a particular variant becomes established in the human population.

DNA can give us clues to our ancestry – for example, the pattern of genetic variants in an individual’s DNA might be more common in people of European ancestry than it is in people of Asian ancestry. In most people, genetic variants in both our nuclear and mitochondrial DNA come from the same part of the world. However, in around one in 40 people in the UK sample, the mitochondrial DNA and nuclear DNA did not have matching ancestries. For example, the nuclear DNA could be European whilst the mitochondrial DNA is Asian. This happens because at some point in the maternal lineage, there was a mother from a different ethnic background.

“As mitochondrial DNA has a much higher mutation rate than nuclear DNA, mutation of the mitochondrial genome is a common occurrence. We wanted to study the natural selective forces determining the fate of these mutations,” says Dr Ernest Turro of the Department of Haematology and the MRC Biostatistics Unit, and one of the senior authors of this study.

“Our statistical analysis suggests that, in people with differing mitochondrial and nuclear ancestries, recent mitochondrial mutations are more likely to have been seen before in populations with the same nuclear ancestry than the same mitochondrial ancestry.”

Crucially, these results suggest that changes in our mitochondrial DNA are shaped by our nuclear DNA.

“This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand,” says Professor Patrick Chinnery, Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and Wellcome Trust Principal Research Fellow. “What this suggests to us is that swapping mitochondria might not be as straightforward as just changing the batteries in a device.”

̽��ֱ��evidence mirrors that from previous studies in fruit flies and mice, where a mismatch between their mitochondrial and nuclear DNA affected how long the organisms lived for and caused cardiovascular and metabolic complications later in life (diseases in humans that might include heart disease and type 2 diabetes, for example).

̽��ֱ��findings could have implications for mitochondrial donation treatment (also known as mitochondrial replacement therapy), says Professor Chinnery, who previously worked with the team at Newcastle ̽��ֱ�� pioneering this treatment. This technique is now licenced for use in the UK to prevent the transmission from mother to child of potentially devastating mitochondrial diseases. It involves substituting a mother’s nuclear DNA into a donor egg while retaining the donor’s mitochondria.

“Mitochondrial replacement therapy is an important new treatment to enable mothers to have children free from terrible mitochondrial diseases, which arise because of severe mutations in mitochondrial DNA,” says Professor Chinnery.

“Our work suggests we’ll need to look carefully at this new treatment to make sure it does not cause unexpected health problems further down the line. It may mean that doctors will need to match the nuclear genome and mitochondrial genome of mitochondrial donors, similar to an organ transplant.”

̽��ֱ��team has now begun work looking at those people whose mitochondrial DNA does not match their nuclear DNA to see if this mismatch increases the likelihood that they will be affected by health problems later in life.

̽��ֱ��research is the first major population study to arise from data collected as part of the 100,000 Genomes Project, which collects genetic data from patients through the NHS with the aim of transforming the way people are cared for and providing a major new resource for medical research. Pilot data for the study was collected through the NIHR Cambridge Biomedical Research Centre.

“ ̽��ֱ��involvement of the 100,00 Genomes Project in major discoveries demonstrates the importance of large-scale, carefully collected datasets with whole genome sequences, which provide new biological insights and pave the way for major healthcare transformations,” says Professor Mark Caulfield, Chief Executive of Genomics England and Co-Director of the William Harvey Research Institute at Queen Mary ̽��ֱ�� of London.

̽��ֱ��research was largely funded by the NIHR, Wellcome, the MRC and Genomics England.

Reference
Wei, W et al. Germline selection shapes human mitochondrial DNA diversity. Science; 24 May 2019; DOI: 10.1126/science.aau6520

Mitochondria, the ‘batteries’ that produce our energy, interact with the cell’s nucleus in subtle ways previously unseen in humans, according to research published today in the journal Science.

This discovery shows us that there’s a subtle relationship between the mitochondria and nuclei in our cells that we’re only just starting to understand

Patrick Chinnery

Dr David Furness (Wellcome Images)

Three mitochondria surrounded by cytoplasm

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