Swap Meet

Study finds "trades" of more than 50 gene variants underlie common blood disorder

Micrograph of disc-shaped red blood cells and ball-shaped white blood cells on colorized blue background
Red and white blood cells. Image: National Cancer Institute/colorized by Broad Communications

Researchers at Harvard Medical School, the Broad Institute of MIT and Harvard and Brigham and Women’s Hospital have uncovered a genetic mechanism that helps drive clonal hematopoiesis, a common age-related condition known to increase the risk of blood cancer and cardiovascular disease.

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In clonal hematopoiesis, or CH, some blood stem cells acquire a mutation that gives rise to cells, or clones, that outcompete normal blood cells.

The new research, which appeared in Nature, shows that clones often swap certain genetic variants on one chromosome arm for those on its counterpart chromosome arm, effectively duplicating one parent’s genetic contribution and erasing the other’s. This swapping helps the mutated blood stem cells outgrow the cells around them.

“This ‘trading up’ of one parent’s gene variants for the other’s generates a substantial fraction of all blood clones,” said senior author Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics in the Blavatnik Institute at HMS and director of genetics for the Stanley Center for Psychiatric Research at the Broad. 

The findings highlight an important interplay between the genetic variation people inherit and the new mutations they acquire during their lifetime.

“Genetics has historically studied acquired mutations and inherited genetic variation separately,” said McCarroll. “These findings help us to think about all of it together, and to think about it in new ways.”

The results also reveal the genetic logic behind a form of mutation that frequently occurs in blood clones and in cancer more generally.

“These kinds of mutations are quite common, but their biological effects had been mysterious,” said first author Po-Ru Loh, associate member of the Broad.

Lifting the hood

Scientific awareness of clonal hematopoiesis emerged over the last decade through a series of studies, including earlier work by McCarroll, Loh and co-author Giulio Genovese, senior computational biologist at the Broad. While the contribution of CH to cancer and cardiovascular disease has become clearer during that time, the biological mechanisms that drive the formation and growth of clones have remained murky.

In the new study, using data from over 480,000 individuals through the UK Biobank, the team found 52 inherited genetic variants in seven genes that led to clones that had swapped inherited variants in consistent ways.

Two of the seven genes regulate stem cell self-renewal, the process by which stem cells divide and generate more stem cells. The scientists discovered that clones manipulate inherited variants in these genes, enabling the clones to self-renew more frequently and expand their numbers relative to normal stem cells.

Another three of the genes limit cell division after DNA damage and the shortening of telomeres, structures at the ends of chromosomes that erode with age. This suggests a second reason for the relatively fast growth of mutant clones: They don’t restrict their growth as they age and experience genetic damage as normal cells do, allowing them to eventually outnumber normal cells. This advantage helps explain why CH becomes far more common in individuals over 50. 

“The genetic effects are converging on pathways that help us understand the biology and the age dependence of clonal hematopoiesis,” said McCarroll.

Value in diversity

The insights came from computational methods the team developed to analyze genetic variation on long chromosomal segments and to study segments, or haplotypes, in addition to individual variants.

“These haplotypes are the true units of genetic inheritance, and often of mutation,” said Genovese, who helped develop the analytical approach.

More discoveries about CH have become possible as genetic samples available for research have expanded and diversified.

For example, the researchers contributed to a related study led by the RIKEN Center for Integrative Medical Sciences in Japan, also published in Nature. That study examined for the first time the genomic landscape of CH in Japanese populations and found that Japanese and European populations tend to acquire clones with different somatic mutations. The results help explain why B-cell lymphoma is common among people with European ancestry, while T-cell lymphoma is common among the Japanese.

“It will be important to embark on more studies like this that inform and learn from populations with diverse ancestries,” said Genovese.

This research was supported in part by the National Institutes of Health (grants DP2ES030554 and R01HG006855), a Burroughs Wellcome Fund Career Award at the Scientific Interfaces, the Next Generation Fund at the Broad Institute, a Glenn Foundation for Medical Research and AFAR Grants for Junior Faculty award, a Sloan Research Fellowship and a U.S. Department of Defense Breast Cancer Research Breakthrough Award (W81XWH-16-1-0316).

Adapted from a Broad news article.