The search for the world’s lost genomes

Data collection

A decade ago, a group of scientists at the Broad Institute in Cambridge, Massachusetts, were frustrated by the fragmented nature of genetics research. While it was easier than ever to study groups of people and identify gene variants that appeared to be associated with a particular disease, there was a growing problem of false alarms.

Geneticists Heidi Rahm and Daniel McArthur came across many gene mutations that were initially linked to rare childhood diseases, but when a larger and more diverse sample of people was examined, the link was rejected.

MacArthur came across a report that evaluated 200 different gene variants that had previously been identified as pathogenic variants, but when analyzed more closely, only nine remained. “We found that if we had more diverse data, we could rule out pathogenicity for more variants, as well as provide evidence for the pathogenicity of variants that actually contribute to disease in different populations, increasing genetic detection rates in those populations,” says Rahm. to give.”

Both Rahm and MacArthur were concerned about the real-life implications of these flaws in genomic science. They heard of patients having abortions based on variants in their DNA that suggested the fetus might be susceptible to serious disease (connections that often turned out to be false alarms). They set out to create a single source of genomic information and combine data collected from studies around the world to provide a resource for geneticists to study a specific gene variant and assess its frequency and pathogenicity in different populations.

This database is called gnomAD and contains more than 70,000 genomes and more than 750,000 exomes (protein-coding parts of the genome). Compared to most large genomic studies, the gnomAD database has been relatively successful in recording information from a more diverse range of individuals. 43% of the data come from non-European Asians, 12.5% ​​from Latinos, 8.8% from Africans or African Americans, and 7.3% from Ashkenazi Jews.

Geneticists around the world have been able to use this information to reclassify gene variants from pathogenic to harmless. “Fixing the problems associated with diversity in data sets is a complex problem, but there have been successes,” says Henriques. “Initiatives such as gnomAD have yielded a large volume of more diverse data that allows for the reclassification of cardiac genes.”

But in terms of understanding genetic diversity, we still lack deep knowledge and there are many unique populations around the world that are almost unstudied.

While new initiatives are constantly being launched (MacArthur is leading a project to sequence Australia’s indigenous and other diverse populations), we have very little genomic data from Oceania, Southeast Asia, North Africa, and the Middle East. The Middle East region is thought to be a valuable source of information because of the high rate of inbreeding where many people share a common ancestor. “This can lead to higher rates of genetic diseases,” Rahm says. “The study of people with genetic diseases can help to identify the causes of the disease and the function of genes affecting the disease.”

But while scientists have become aware of this issue, efforts to collect genetic information of different communities have been hampered by political tensions, economic crises and conflicts in many countries of the region.

Negative attitudes about genetic diseases often discourage families from participating in research projects, while international collection initiatives such as gnomAD have found that Middle Eastern countries are either unwilling or unable to share their genomic data.

As a result, some of the biggest advances have come from active efforts to improve study diversity in Europe and the US with the US National Institutes of Health’s new All of Us program specifically targeting groups for which limited genomic information is available.

Genomics England has launched studies to understand and find ways to overcome barriers to participation in genetic research for British citizens of African or Caribbean descent. “One of the reasons for the lack of diversity in genomic studies is the recruitment process,” says Henriques.

Effective dialogue with communities and populations that are excluded from research, as well as improving the participation of ethnic groups in the clinical workforce, is important, as this improves the participation of study participants.

But the distant future of genomic research, especially in the African continent, seems more vulnerable. While H3Africa has received $176 million from the National Institutes of Health and the Wellcome Trust over the past ten years, this funding ends in 2022 and its future is uncertain. There are reports of African professors who have received funding as part of H3Africa but have chosen to move away from human genetics and focus on less expensive subjects such as studying the genomes of drug-resistant bacteria.

Some have even questioned the value of investing in genetic research, arguing that such money would be better spent on projects like anti-smoking campaigns and healthy eating that provide more immediate public health benefits.

Attitudes may change if Nigeria’s 100,000 Genomes Project provides data that can be used to find and validate new drug targets, but even this pioneering initiative may be vulnerable to external forces.

While 54gene, which is sponsoring the project, has received significant funding from international investors, the company was forced to lay off 200 employees amid the economic turmoil of 2022, and their economic value has declined.

Experts say funding for these studies is critical to improving the future of medicine around the world. As Rahm predicts, one important consequence of improving the diversity of genetic research is that doctors will soon no longer use ethnicity to make clinical decisions. “In the past, ethnicity has been used in certain areas of medicine, and there’s a lot of data showing that this practice is problematic,” he says. We need to identify real differences, such as genetic factors and environmental factors, and use objective and robust criteria to make decisions, rather than using inferences based on ethnic background, which are fraught with problems.”

Fatomo feels we are moving in the right direction, noting that before Nigeria’s 100,000 Genomes Project, the largest sequencing study in Africa involved only 6,400 people. But he warns there is still a long way to go. “According to an article published in Nature, in order to get the genetic diversity of the African continent, three million genomes on the continent need to be sequenced,” he says. “We have a long way to go to address genomic inequality, but more efforts must be made now.”

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