Proteins create patchwork with DNA

Breaking new ground 28. sep 2020 4 min Professor in Molecular Genetics, NNF Young Investigator Eva Ran Hoffmann Written by Kristian Sjøgren

Before a sperm and an egg join to create a new life, DNA is cut into pieces and then reassembled. New research shows how.

We all consist of genes from our mother and father. The sperm brings Dad’s genes, and Mom’s genes are in the egg.

Before the sperm and the egg meet in the uterus and their genetic material combines, the DNA from each parent have been broken up and recombined as a patchwork of genes.

This patchwork gives each of us our unique genetics, and now researchers have figured out how the DNA breaks are repaired.

“We have long known that the genes from our mother and father are combined into new chromosomes in our eggs and sperm and that this is an important evolutionary mechanism. But we had not fully understood how this is orchestrated so that combining the genetic material does not lead to the development of disorders such as Down syndrome, Klinefelter syndrome or Turner syndrome,” explains a Danish contributor to the new study, Eva Hoffmann, Professor at the Department of Cellular and Molecular Medicine, University of Copenhagen.

The research results were published recently in Nature.

Mother’s and father’s genes combine in different ways

The research is specifically about chromosomes – long chains of genetic material that are bound together in well-defined structures.

Humans have 23 chromosome pairs; one pair is the sex chromosomes.

Each chromosome contains many genes, and it can be tempting to think that, in chromosome pairs, one chromosome that we pass on to our children would come from either our mother or from our father.

This is partly true, however, in our eggs and sperm, each chromosome that we inherited from our parents has been divided into smaller pieces and then recombined to generate new chromosomes that consist of DNA from both our mother and our father.

For example, parts of chromosomes 1 in eggs or sperm come from our mother’s lineage and other parts from our father’s.

Chromosomes therefore comprise larger patchworks of elements inherited through the generations.

“Genetic studies show that each chromosome is a combination of chromosome elements from both the mother’s and the father’s lineage, but the mechanism by which the chromosomes cross over had been unknown,” explains Eva Hoffmann.

Relevant to evolution and genetic diseases

The great interest in how genes recombine has various perspectives.

Some researchers want to understand how chromosomes combine because this is an evolutionary mechanism that is just as crucial as mutations.

Randomly combining the chromosomes changes the genes inherited through the generations.

This means that the genes passed on to a child are not either the father’s or mother’s genes but a combination of both. This gives evolution much more leeway to try new combinations of genes in order to constantly stay ahead in coping with the challenges that an organism may encounter.

In the interest of advancing medical science, other researchers are interested in understanding how chromosomes combine because this is a process that malfunctions when children are born with various genetic syndromes.

This can include Down syndrome, in which the child has an extra chromosome 21; Klinefelter syndrome, in which the child is born with an extra sex chromosome; or Turner syndrome, in which a sex chromosome is missing.

These three syndromes are caused by errors in the exchange of chromosome elements between the chromosomes so that the fetus develops with either one chromosome too many or one too few.

Other diseases may result from minor defects in breaking and recombining the chromosomes, in which elements of a chromosome are not removed or inserted into the genome.

“For some chromosomes, you do not want too many changes, but breaking and recombining relatively often is an advantage for others. For example, swapping things around may be advantageous for chromosomes containing many of the genes of the immune response because this may produce better defence against external threats,” says Eva Hoffmann.

Proteins make and repair 600 breaks in the DNA

Before the egg and sperm meet, the DNA is broken up to 600 times. The fragments are then recombined, so that elements from one chromosome are replaced with elements from the other.

In the study, the researchers discovered how enzymes catalyse the repair to ensure that chromosomes recombine and form crossovers. This generates new chromosomes with new properties.

Researchers have long known about some of the genes involved in the above process such as MSH4 and MSH5, which are expressed as proteins that stabilize the processes when the cells break their DNA.

The MSH4 and MSH5 proteins ensure that the chromosome breaks are repaired and the new research shows that two other proteins, MLH1 and MLH3, make the final cut to separate the two chromosomes that recombine.

“These four proteins play a role in all chromosome crossovers and ensure that the process involves an actual crossover and do not simply repair the chromosome once it has been broken, which would not achieve the required crossover of DNA,” explains Eva Hoffmann.

Proteins influence various important life processes

Although researchers have identified the new function of MLH1 and MLH3, these proteins are actually known.

Both proteins play a role in the mismatch repair system that edits the genes if recombination errors have been made.

When the DNA is copied, MSH2 and MSH6 examine it for defects, and if they discover problems, they recruit MLH1 and MLH3 to make the surgical incision in the same way as in the chromosome puzzle.

“MLH1 and MLH3 play a key role in ensuring that no mistakes are made or mutations arise in breaking or repairing the DNA. This is why cancer can develop when these two proteins do not function correctly,” says Eva Hoffmann.

Improved understanding of the reasons for infertility

Eva Hoffmann says that the new discovery gives researchers good basic understanding of what happens in the egg and sperm before they meet.

This understanding may advance knowledge of what is going on, for example, when men and women are wholly or partly infertile. This may result from genetic components, in which defects in the chromosome crossover arise before fertilization, even though both the egg and the sperm appear to be fully functional.

The mechanism also plays a role in the whole system that keeps a woman’s eggs free from defects for the many years before she reaches childbearing age.

“These recombination reactions act as physical anchors to prevent chromosome defects while the egg is dormant. The more of these systems we have, the better the eggs. The older women get, the worse these systems work, and women therefore have more chromosome defects as they get older,” says Eva Hoffmann.

Regulation of the MLH1–MLH3 endonuclease in meiosis” has been published in Nature. In 2015, the Novo Nordisk Foundation awarded a grant to Eva Hoffmann for the project Mapping the Genomic Landscape in the Human Germline. Eva Hoffmann was recently elected as a member of the European Molecular Biology Organization, a lifetime honour in recognition of her extraordinary results within the biological sciences.

Chromosomes are rearranged and organized into new sets to create diversity as they are passed from parent to offspring through the germline. The genet...

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