How hot spots of genetic variation have evolved in human DNA

BUFFALO, N.Y. – What differentiates one person from the other and how have these differences evolved?

A study by biologists at the University of Buffalo illuminates one aspect of this complex issue. The research examines hot spots of genetic variation in the human genome, examining sections of our DNA that are most likely to differ significantly from one person to the next.

The findings reveal a complex evolutionary story, highlighting the malleability of human DNA and showing how adaptable we are – but delicate species.

"We have made some progress in understanding how genome variations are occurring," says Omer Gokcumen, PhD, badistant professor of biological sciences at the UB College of Arts and Sciences. "Which parts of the genome are protected and conserved during evolution? Which parts are not protected and why?

"Previous work has shown that structural variations – deletions, duplications, other changes in DNA – are not evenly distributed in the genome.There are deserts and hot spots.The big question is whether this clbadification is of biological significance, whether it is random or driven by evolutionary forces, our research is about this issue. "

The study, published online March 18 in the newspaper Genome biology and evolutionled by Gokcumen and UB PhD student Yen-Lung Lin, who has since graduated and will soon begin a new postdoctoral position at the University of Chicago.

Explore the architecture of thousands of genomes

The human genome is the entirety of a person's DNA. Genes – DNA fragments that affect features such as eye color and risk of disease by telling our body how to build important proteins – make up about 1.5% of our genome. The rest consists of non-coding DNA, whose function (or lack thereof) is the subject of debate between scientists.

Each person's genome is different and the new study compared the DNA of more than 2,500 people.

Scientists focused on those sections of the genome that differ most from person to person, identifying 1,148 areas harboring an unusually high number of structural variants, including pieces of sections of the genome. Duplicate, deleted, inserted, inverted or repeated DNAs.

New perspectives on the malleability of human DNA

An examination of these "hot spots" revealed a complex evolutionary history.

Most are found in gene-poor genome regions, as expected. (Gene modification can lead to devastating health problems, so it makes sense that gene-rich areas tend to be more conservatively conserved during evolution, Gokcumen explains.)

However, a small subset of structural variant hot spots is found in parts of the genome that harbor important genes. According to this study, genes related to our sense of smell, our blood and skin functions and our immunity to disease are overrepresented.

Balanced selection – in which evolving dueling forces push a species to preserve a range of traits – can help explain why these hot spots, which carry genes, exist.

An example: in the study, a deletion of DNA increasing the risk of suffering from a blood disease called thalbademia was discovered in about 16% of the genes of populations in sub-Saharan Africa. Although evolution largely eliminates this genetic variation in human societies from other parts of the world, the variation persists in sub-Saharan Africa because it is valuable in this country, says Gokcumen: Deletion can confer a resistance to malaria, a major disease in the region.

"There is an evolutionary reason why this mutation is persistent, despite its perverse effects," he says. "It's actually also beneficial, at least for some populations." The balance of selection is important for adaptation, and we think it contributes to the development of some structural variants of hot spots. "

If the results on balanced selection demonstrate the adaptability of humanity, a second result of the study suggests how delicate we are – how easily problems can occur.

The conclusion is related to the malleability of human DNA and the possibility that some hot spots of variation are located in sections of the genome that are, for biochemical reasons, more likely to be altered.

In most people, genetic mutations in these areas are not devastating. But in some cases, large genetic deletions that start in one hotspot and end in another may result in the erasure of whole genes in between, resulting in health complications, Gokcumen explains.

An example: the study revealed that a number of consecutive variant hot spots were found on both sides of the small SHOX (Home Stox) gene, the deletion of which could lead to a serious bone growth disorder. resulting in a very small size. In some people in whom the SHOX gene is absent, DNA deletions started in a hotspot, extending over the entire SHOX gene and ending with a second hotspot.

When Gokcumen and Lin performed statistical tests, they found that the starting points and onset of large gene mutations of known medical interest were found more often than expected in structural variant hot spots.

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The study was funded by the National Science Foundation.

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