In the world, one out of 700 children are born with Down syndrome. A syndrome, where the child has an extra copy of chromosome 21, resulting in 47 chromosomes instead of 46. This typically results in characteristic physical features and some level of learning disability.

But newborns with Downs syndrome also tend to have an elevated number of red blood cells, and as they grow older, they face a 150-fold higher risk of developing leukemia compared to those without the condition.

“Our study revealed that the additional chromosome 21 alters how DNA is packed inside the cells. This difference affects how certain genes are regulated and can contribute to the development of leukemia,” explains Rebecca Moller, one of the researchers from University of Copenhagen behind the new study.

To more precisely understand the impact of the extra chromosome 21, the researchers sequenced the genes of over 1.1 million cells from fetuses with and without Down syndrome.

“Interestingly, the dysregulations are not uniform and vary depending on the cell type and its environment. We found for example that blood stem cells in individuals with Down syndrome show dysregulations of genes involved in making red blood cells, explaining the symptoms in newborns” says Professor Ana Cvejic, the senior lead scientist from University of Copenhagen.

Too many cellular “powerhouses”

The researchers also identified another crucial difference in the blood stem cells of people with Down syndrome: an increased number of mitochondria, the “powerhouses” of the cells that generate energy.

While energy production is vital, too many mitochondria can damage a cell and its DNA by producing harmful molecules.

“These harmful molecules, called reactive oxygen species, are known to attack DNA creating mutations that can lead to pre-leukemia and, eventually, leukemia.” explains Dr Andrew Marderstein, from Stanford University and the first author in the study.

The findings from the study underscore the importance of understanding the intricate relationship between genetics and the cellular environment of blood cells in individuals with Down syndrome.

“This study is the largest of its kind, and it shows that the environment and genetic makeup of cells are crucial in understanding how blood cells and leukemia develop. Understanding these mechanisms is essential for guiding future research in stem cell biology and cancer,” says Professor Ana Cvejic, who emphasizes that these insights pave the way for a better comprehension of disease development in Down syndrome.

The study ‘Single-cell multi-omics map of human fetal blood in Down syndrome’ has been published in Nature.