Unpacking luck in the genetic lottery

February 06, 2023

Sarah Kim-Hellmuth joined such a team as a postdoctoral researcher at the recently founded New York Genome Center in 2015. It found that “the genetic regulation of gene expression occurs much more frequently than had previously been assumed,” explains Sarah Kim-Hellmuth. In 2022, she received the prestigious Emmy Noether grant by the German Research Foundation (DFG), which has since funded her research group. Ability to predict which symptoms a patient will develop When the GTEx analyses were completed in 2020, Sarah Kim-Hellmuth came back to Munich. In 2022, she received the prestigious Emmy Noether grant by the German Research Foundation (DFG), which has since funded her research group.

Some people almost never fall ill. While others struggle from one cold to the next. There are people who have never Covid-19 during the entire pandemic. But then there are people who have caught it for the third time. Our genome plays a decisive role in these differences. However, the cause cannot be pinpointed to a single gene. Whether we generally stay healthy or catch every infection is influenced by millions of loci in our genome. Polygenetic risk is the technical term for this phenomenon.

“I have a knack for big data” says human geneticist Sarah Kim-Hellmuth, who carries out complex analyses to investigate the genetic influence on the human immune system and on the course of various diseases.

© Stephan Höck / LMU

Human geneticist Sarah Kim-Hellmuth studies this exciting topic in her research. She wants to understand why, for example, one person develops an autoimmune disease while the next does not. Why the same disease cause very different symptoms in different people. And how we can best help these patients. Using computer algorithms, she analyzes huge datasets to identify connections between a person’s genome and their disease risk, with the goal of developing personalized therapeutic approaches. Her focus is on autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, but also on cardiovascular and metabolic diseases.

“Gene activity plays a major role in disease development,” explains Kim-Hellmuth. To understand this, we need to look at how the genome works. Although every cell in our body carries the same DNA, the cells in various tissues – such as those of the heart, blood, and brain – are quite different from each other. They have different shapes, capabilities and functions. This is the result of genes being read in an extremely specific way. They are active only at a specific time and in a specific place. Otherwise, they lie dormant. As such, people differ not only in which genes they have, but in when these genes are active or inactive.

The genetic regulation of gene expression occurs much more frequently than had previously been assumed. Our study showed that almost every single gene of the over 23,000 analyzed genes has a genetic regulatory variant in at least one of the tissues.
Dr. Sarah Kim-Hellmuth

A hundred thousand base pairs away from the gene

What nature asks of us

Read the answers in the new issue of our research magazine EINSICHTEN at www.lmu.de/einsichten. | © LMU

The human genome consists of around three billion building blocks known as DNA bases. Only one to two percent of them are actually genes that are transcribed from DNA to RNA and ultimately to proteins. However, the remaining 98 percent are not junk, as was long thought. For one thing, they contain so-called promoters and enhancers, which regulate the activity of genes.

If even just one base is changed in these promoters or enhancers, this can influence how well or poorly the gene they regulate is read. There are around five million such variable positions in the population. Some changes strengthen gene expression, while others weaken it. Often the same gene is regulated from different places in the genome, which could be right next to the gene or a hundred thousand base pairs away, making this regulation extremely complex. To be able to identify a connection between a change in the genome and the occurrence of a disease, you need to investigate the genomes of many people. One scientist alone cannot do this – teamwork is needed.

Sarah Kim-Hellmuth joined such a team as a postdoctoral researcher at the recently founded New York Genome Center in 2015. “The atmosphere was like in a start-up,” recalls Kim-Hellmuth. Young group leaders, people exchanging ideas, a hive of activity, innovative technologies, flat hierarchies. “Two doors down, there were Nobel laureates whom I could ask for advice,” she remembers with fondness. Together with about 50 other scientists from around the world, she worked on the Genotype-Tissue Expression (GTEx) project. Although she had not had much computational expertise, she rose to become one of the lead analysts at GTEx. “I have a knack for Big data” is her simple explanation.

The GTEx group had collected tissue samples from 838 donors: biopsies from the lung and pancreas, adrenal gland and liver, esophagus and brain – in total, 15,201 specimens from 49 tissues. They carried out two different analyses on all samples. DNA sequencing reads the DNA sequence of cells. This is identical in all tissues from a donor. RNA sequencing, by contrast, reveals which areas of the DNA are actually active in the individual tissues. There are huge differences between tissues of the same individual.

Sarah Kim-Hellmuth leads her own research group at the Dr. von Hauner Children’s Hospital. The group is funded by the German Research Foundation (DFG):

© Stephan Höck / LMU

Who has a higher individual risk than the rest of the population?

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In 2020, the consortium published its most extensive data analysis yet. It found that “the genetic regulation of gene expression occurs much more frequently than had previously been assumed,” explains Sarah Kim-Hellmuth. “Our study showed that almost every single gene of the over 23,000 analyzed genes has a genetic regulatory variant in at least one of the tissues.” Formerly, it was thought that, at the most, half of all genes are regulated by genetic variants. With this huge dataset, GTEx laid the foundation for scientists all over the world to be able to search in a more targeted fashion for the influence of genetic variation on gene regulation.

Indeed, for some diseases, scientists can already say who is particularly at risk, and who was luckier in the genetic lottery. Coronary heart disease is one such affliction. Around eight percent of men and women in Germany are three times more likely to develop coronary heart disease than the rest of the population based on their genetic profile alone. As it is not just one or two genes that are responsible for this, medical professionals use the term polygenetic risk factors. Although this risk is written into the genome, people can improve their situation by pursuing a healthy lifestyle. With physical activity and eating well, they can reduce their risk by a considerable margin.

And then there is breast cancer. Women with certain mutations in the genes BRCA1 and 2 have an elevated risk of developing breast and ovarian cancer. But numerous other genes also come into the equation. “The polygenetic risk factors for this disease can be low even for people with mutated BRCA1 and 2,” explains Kim-Hellmuth. When this is the case, doctors and patients might choose a somewhat more conservative approach.

Even patients with the same disease can exhibit very different symptoms. It would be a huge leap forward if we could not only diagnose it, but also take into account the genetic contribution to the disease so that we could predict which symptoms a patient might develop.
Sarah Kim-Hellmuth

GTEx also revealed that gene regulation differs between the sexes. 37 percent of all investigated genes were read differently in at least one tissue, depending on whether the person was a woman with two X chromosomes or a man with an X and a Y chromosome.

When the GTEx analyses were completed in 2020, Sarah Kim-Hellmuth came back to Munich. She had formerly studied medicine at LMU and the Technical University of Munich (TUM). She resumed her clinical work at the Dr. von Hauner Children’s Hospital, where she leads her own research group with a joint affiliation at Helmholtz Munich since 2021. In 2022, she received the prestigious Emmy Noether grant by the German Research Foundation (DFG), which has since funded her research group.

Whereas her work in New York involved all kinds of human body tissues, her current focus is on the human immune system. Even taken on its own, the immune system is extremely variable and complex, as it consists of many different cell types each of them with a different function. Identifying the genetic influence on immune cells, and thus the diseases process, requires large amounts of data.

Ability to predict which symptoms a patient will develop

When the GTEx analyses were completed in 2020, Sarah Kim-Hellmuth came back to Munich. She had formerly studied medicine at LMU and the Technical University of Munich (TUM). She resumed her clinical work at the Dr. von Hauner Children’s Hospital, where she leads her own research group with a joint affiliation at Helmholtz Munich since 2021. In 2022, she received the prestigious Emmy Noether grant by the German Research Foundation (DFG), which has since funded her research group.

Whereas her work in New York involved all kinds of human body tissues, her current focus is on the human immune system. Even taken on its own, the immune system is extremely variable and complex, as it consists of many different cell types each of them with a different function. Identifying the genetic influence on immune cells, and thus the diseases process, requires large amounts of data.

“Even patients with the same disease such as systemic lupus erythematosus can exhibit very different symptoms,” explains Kim-Hellmuth. “It would be a huge leap forward if we could not only diagnose lupus, but also take into account the genetic contribution to the disease so that we could predict which symptoms a patient might develop.” Then doctors could plan their treatment to specifically target or prevent these symptoms.

For the future, Sarah Kim-Hellmuth aims to study immune response differences in the global population. “The prevalence of autoimmune diseases and disease courses are very different across the world,” explains Kim-Hellmuth. She would like to understand where these differences come from and how large the genetic influence is.

But this complex research requires funding. Sarah Kim-Hellmuth is currently applying for a highly prestigious Starting Grant from the European Research Council (ERC), which would provide funding of up to 1.5 million euros. In the project, she plans to obtain immune cells from people from Africa, Asia, and Europe, study their immune responses, and then compare these with their genomes. “Because I also did a lot of research into sex differences within the GTEx project – and because the immune system of men and women are so different – this question will continue to be part of my research.”

Claudia Doyle

© Stephan Höck / LMU

Dr. med. Sarah Kim-Hellmuth is a human geneticist. Since the start of 2022, she leads an Emmy Noether research group at the Dr. von Hauner Children’s Hospital at LMU and at the Institute of Translational Genomics at Helmholtz Munich. The group studies the genetic influence on the human immune system. Since 2022, she has been a member of Die Junge Akademie, an academy for outstanding young researchers supported by the Berlin-Brandenburg Academy of Sciences and Humanities and the German National Academy of Sciences Leopoldina.

Read more articles of the current issue and other selected stories in the online section of INSIGHTS/EINSICHTEN. Magazine.