Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and ...

Scientists Find Evidence Of Rare Genetic Disorders In Ancient Bones

By Xochitl Bott Rivera

Xóchitl Bott Rivera is a trending news intern at Deseret News and currently covers science and tech news.

A new study published in the journal Nature Communications reveals that scientists have identified ancient skeletal remains with Down syndrome and the even rarer Edwards syndrome.

Researchers even found evidence that individuals with these syndromes were taken care of in ancient times.

What scientists found in the bones

According to Smithsonian Magazine, scientists from around the globe tested the skeletal remains of more than 10,000 people. Specifically, they took DNA samples from the bones and tested them for genetic disorders.

Scientists "screened the DNA extracted from human remains from the Mesolithic, Neolithic, Bronze and Iron Ages all the way up to the mid-1800s," said Adam Rohrlach, a researcher involved in the study, in a statement from the University of Adelaide.

By testing the DNA for the additional chromosomes that cause genetic disorders, scientists were able to identify six skeletal remains with Down syndrome and one with Edwards syndrome, per the University of Adelaide. Determining if ancient remains have genetic disorders, specifically Down syndrome, is a difficult task for scientists due to the variety of symptoms, per Smithsonian Magazine.

Rohrlach said, "While we expected that people with Down syndrome certainly existed in the past, this is the first time we've been able to reliably detect cases in ancient remains, as they can't be confidently diagnosed by looking at the skeletal remains alone," per Smithsonian Magazine.

What is Down syndrome and Edwards syndrome?

According to the Mayo Clinic, Down syndrome is a genetic disorder that occurs when the body creates an extra copy of chromosome 21. Symptoms vary from person to person, but some common ones include learning disabilities, heart defects, small heads and shortened height. Down syndrome is often caused by irregular cell division.

Edwards syndrome is a rarer genetic disorder. Caused by an extra copy of chromosome 18, babies diagnosed with Edwards syndrome often don't survive full term, according to Cleveland Clinic, with most of them dying as stillborns or miscarriages. If a child does survive birth, common symptoms include club feet, low-set ears and abnormal organs. Most do not survive past their first year.

How does this discovery change the way we perceive ancient societies?

The seven babies with genetic disorders that were identified in the new research all came from different time periods and civilizations, according to Smithsonian Magazine:

Three babies with Down syndrome were dated back to the Iron Age in what is now Spain (and most likely did not survive to birth).

Three additional children under the age of 1 with Down syndrome were found in three separate locations:

The Greek Island Aegina, dated to about 3,300 years ago.

A site in Bulgaria that dates back to the Bronze Age.

A church graveyard in Finland dating between the 17th and 18th centuries.

A baby with Edwards syndrome was found in Spain at a Bronze Age site, with researchers believing it most likely did not survive past 40 weeks of gestation.

Across these multiple gravesites, researchers noticed how the children were buried with much care and special gifts. Rohrlach said, "These individuals were buried according to either the standard practices of their time or were in some way treated specially. This indicates that they were acknowledged as members of their community and were not treated differently in death," per University of Adelaide.

Over One Hundred New Genetic Links To Abnormal Micronuclei Are Found

Most cells in the human body carry the entire genome within their nucleus, and as cells divide, age, or are exposed to environmental stresses like UV rays, the DNA in that nucleus can become damaged. Cells have a variety of ways to repair different errors that can arise in DNA. Micronuclei, for example, contain genetic material that should be sequestered in the nucleus, but has been misplaced. The presence of micronuclei in cells has been linked to a variety of disorders including some types of cancer and developmental diseases.

In a series of experiments in which the activity of over 1,000 genes was each systematically knocked out, scientists have now identified 145 genes that are associated with the formation of micronuclei in mouse cell lines. The findings have been reported in Nature.

When a gene called DSCC1 was ablated, there was an increase in genomic instability. In mice without DSCC1 expression, the animals displayed symptoms of diseases known as cohesionopathies. These diseases are caused when cohesin proteins are dysfunctional, leading to chromosome disorganization, and improper segregation of the genome in dividing cells. This is a serious problem for cells, and can increase the risk of developmental problems including growth retardation,  distinctive facial features, and intellectual disability.

But the effects of the loss of DSCC1 could be partially rescued by removing a protein called SIRT1. The removal of SIRT1 was found to reduce levels of DNA damage. The deleterious impact of DSCC1 knockdown was rescued with SIRT1 knockdown, because of the restoration of a protein called SMC3.

The findings helped shed new light on genetic factors that influence the health of the human genome over a lifetime, how diseases develop as the genome loses integrity, and may open up new treatment options for cohesinopathies.

"Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions," said senior study author Professor Gabriel Balmus of the UK Dementia Research Institute at the University of Cambridge. "Our study underscores the potential of SIRT inhibitors as a therapeutic pathway for cohesinopathies and other genomic disorders. It suggests that early intervention, specifically targeting SIRT1, could help mitigate the biological changes linked to genomic instability before they progress."

Sources: Wellcome Sanger Institute, Nature

The Use Of Genetics For Disease Prediction Improves For Ten Disorders

The ability to predict a person's risk of certain disease with genetics has sometimes been overstated, but in recent years, human genetic data has become truly useful information in the clinic.  While humans carry more or less the same genes in their genome, there can be small differences, or variations in the sequences of their DNA. Some of those variants have very little or no biological impact while others can be extremely significant; it all depends of what the variant is and where it happens.

Researchers have analyzed many significant variants in human DNA, and some have been linked to an increase or decrease in a person's likelihood of developing a disease. When the sequence of the human genome and the variants it holds is used to determine a person's risk of disease, that is a so-called polygenic risk score, and these scores have been developed for dozens of human disorders like diabetes, heart disease, and kidney disease. But it is not always easy to use that genetic information to make decisions in the clinic.

Scientists have now outlined tests that have been evaluated, and validated. They can help determine polygenic risk scores for ten common diseases, and the research team also ensured that the scores can be used in patients without European ancestry. The investigators analyzed the genetic and health data of 25,000 people in an effort to improve the use of genetic data in the clinic, and its ability to improve patient's lives. The work has been reported in Nature Medicine.

The suitability of polygenic risk scores for use in the clinic has been debated, and in many cases, they have only been developed with genetic data from people with European ancestry. "With this work, we've taken the first steps toward showing the potential strength and power of these scores across a diverse population. We hope in the future this kind of information can be used in preventive medicine to help people take actions that lower their risk of disease," noted first study author Niall Lennon, the chief scientific officer of Broad Clinical Labs, among other appointments.

The investigators looked for risk scores that had been created with data from people with two or more ancestries. They also identified polygenic scores that were useful, because they had been linked to strategies for preventing the diseases they predicted, whether through lifestyle changes or treatments.

"It was important that we weren't giving people results that they couldn't do anything about," said Lennon.

Polygenic risk scores for asthma, atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, type 1 diabetes, obesity, and type 2 diabetes were the focus.

Lennon acknowledged that they cannot correct all biases in the data, but they can ensure that people who are in high risk categories will be identified regardless of their ancestry.

Now the researchers are going to follow up with the people whose genetic data was used for the study, and they want to know more about how this information might inform their healthcare decisions.

"Ultimately, the network wants to know what it means for a person to receive information that says they're at high risk for one of these diseases," Lennon explained.

Sources: Broad Institute of MIT and Harvard, Nature Medicine

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