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Source: Charite – Universitatsmedizin Berlin Multipliers and inversions of DNA sections lead to the masculinization of female moles Blind and wild: The Iberian mole (Talpa occidentalis), which is widespread in Spain and Portugal, has a special characteristic: the females develop strong muscles and testicular tissue due to an increased Level of male sex hormones. Photo: David Carmona / Department of Genetics, University of Granada, Spain Within topologically associated domains (TADs, represented by triangles), genes and their regulators interact with one another. Regulators are often tissue-specific and activate their associated genes accordingly, and genomic inversion can alter this organization. Certain regulatory elements can be linked to another gene and thereby activate it in other tissues. Graphic: Thomas Splettstoesser / MPIMG In mice, the activation of the CYP17A1 gene by a genetic regulator leads to the production of testosterone. Moles have several of these activating sequence sections, which means that the animals produce more testosterone. Graphics: Francisca M. Real, Darío Lupiáñez / MPIMG Joint press release by Charité – Universitätsmedizin Berlin, the Max Planck Institute for Molecular Genetics and the Max Delbrück Center for Molecular Medicine Female moles have ovarian tissue as well as testicular tissue that produces male sex hormones – which makes them deviate from the categorization into two genders. A team led by the Berlin researcher Prof. Dr. Stefan Mundlos and Dr. Darío Lupiáñez in Science *. Moles are special creatures that cavort in an extreme habitat. As miners deep in the earth, they have an extra finger on each front paw and exceptionally strong muscles. In addition, female moles are bisexual, but the animals remain fertile. As is typical of mammals, they are endowed with two X chromosomes, but have both functioning ovarian and testicular tissue. In moles, both types of tissue are united in one organ, the ovotestes – and that is unique among mammals. The testicular tissue of female moles does not produce sperm, but does produce large amounts of the sex hormone testosterone, so that the females have similar levels to the males. Presumably this natural “doping” makes the female moles aggressive and muscular, which is an advantage for a life underground, where they dig caves and fight for resources. In a study in the journal Science, scientists from Berlin report on the genetic peculiarities that lead to the characteristic sexual development in moles. Accordingly, it is primarily changes in the structure of the genome that lead to a change in the control of gene activity. In addition to the genetic program for testicular development, this also stimulates the enzymes for the production of male hormones in the females. The study by an international team was carried out under the direction of Prof. Dr. Stefan Mundlos, Director of the Institute for Medical Genetics and Human Genetics at Charité – Universitätsmedizin Berlin and research group leader at the Max Planck Institute for Molecular Genetics (MPIMG), and Dr. Darío Lupiáñez, research group leader at the Berlin Institute for Medical Systems Biology (BIMSB), which belongs to the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Genetic material emerged that was passed on to the next generations, ”says Prof. Mundlos. “But how are DNA changes and characteristics specifically related and how do you find them?” To answer this question, the researchers sequenced the genome of the Iberian mole (Talpa occidentalis) completely for the first time. They also examined the three-dimensional structure of the genetic material in the cell. Because in the cell nucleus, genes and associated control sequences form regulatory domains – these are relatively isolated “neighborhoods” in which DNA segments interact with one another particularly frequently. “Our hypothesis was that there are not only changes in the genes of the mole, but also, above all, in the regulation of these genes,” says Prof. Mundlos Larger parts of the genome are also shifting, says the researcher. If DNA segments get from one place to the next, completely new regulatory domains can arise and thus activate new genes or strengthen or weaken existing ones. “Mammalian sexual development is complex, but we have a pretty good idea of ​​how the process works,” says Dr. Lupiáñez. “From a certain point in time, development continues in one direction or the other, male or female. We wanted to know how evolution modulates this actually established process and enables the intersexual properties of moles. ”In fact, when comparing the genome of other animals and humans, the team discovered an inversion – that is, an upside-down section of genetic material – in an area that is adjacent to the Formation of the testicles is involved. As a result of the rotation, additional DNA sections get into the regulatory domain of the FGF9 gene, which reorganizes the control and regulation of the gene. “This change means that in female moles not only ovarian tissue can develop, but also testicular tissue,” explains the study’s lead author, Dr. Francisca Martinez Real, scientist at the MPIMG and at the Institute for Medical Genetics and Human Genetics at the Charité. In addition, the team discovered that a section of the genome has tripled around the gene CYP17A1, which is responsible for the production of male sex hormones (androgens). “The triplication results in additional control sequences for the gene – and in the ovotestes of the female moles, more male sex hormones are produced, especially more testosterone,” says Dr. Real. One challenge of the study was that the very territorial moles could not be kept in the laboratory. “We had to do all the tests on wild moles,” says Dr. Lupiáñez. He and Dr. Real were traveling in southern Spain for months, collecting samples for their experiments. “However, this difficulty was also a strength of our study. Our results apply not only to laboratory animals, but also to animals living in the wild. ”The two genome changes actually contribute to the special sexuality of female moles. The research group proved this by imitating the genetic changes from the moles in the mouse model. The female mice had elevated androgen levels that were as high as those of normal male mice. They were also significantly stronger than unchanged conspecifics. In moles, the sexes are not clearly demarcated from one another, rather the females move on a spectrum between typically female and typically male, i.e. they are intersexual. “Our findings are a good example of how important the three-dimensional organization of the genome is for evolution,” says Dr. Lupiáñez. “Nature makes use of the existing toolbox of developmental genes and only rearranges them in order to create a characteristic such as intersexuality. Other organ systems and their development are not affected. ”“ Historically, the term intersex has triggered considerable controversy, ”says Prof. Mundlos. “There was and is the tendency to characterize intersex phenotypes as pathological conditions. Our study shows how complex sexual development is and that nature can produce a wide range of intermediate types. ”* Real FM et al. The mole genome reveals regulatory rearrangements associated with adaptive intersexuality. Science 2020. doi: 10.1126 / science.aaz2582

Charité – Universitätsmedizin BerlinThe Charité – Universitätsmedizin Berlin is one of the largest university clinics in Europe with around 100 clinics and institutes on 4 campuses and 3,001 beds. Research, teaching and health care are closely networked here. With an average of around 15,500 employees across the Charité and 18,700 employees from over 100 nations across the Group, the Berlin University Medical Center is one of the largest employers in the capital. 4,553 of the employees worked in the care sector and 4,454 in the scientific and medical sector. In the past year, 154,261 inpatient and partial inpatient cases and 700,819 outpatient cases were treated at the Charité. In 2019 the Charité achieved total income of around 2.0 billion euros, including third-party funding and investment grants. With the 179.1 million euros raised in third-party funding, the Charité set a new record. At the medical faculty, which is one of the largest in Germany, more than 8,000 students are trained in human medicine, dentistry and health sciences. In addition, there are 644 training positions in 9 health professions. www.charite.de The Max Planck Institute for Molecular Genetics (MPIMG) The Max Planck Institute for Molecular Genetics (MPIMG) is concerned with the investigation of the function and control of the genome – especially during embryonic development, differentiation processes, the Organ development and the emergence of diseases. Genes and genomes are examined using automated methods, high-throughput technologies and various model systems. Bioinformatic methods are used to evaluate and interpret the data. The close connection between experiment and bioinformatics is typical for the work of the MPIMG. Around 350 people work in the research institute, which was founded in Berlin-Dahlem in 1964, and cultivate a culture of interdisciplinarity and innovation. www.molgen.mpg.de The Max Delbrück Center for Molecular Medicine (MDC) The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in 1992 in Berlin. It is named after the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC’s task is to research molecular mechanisms in order to understand the causes of diseases and to better diagnose, prevent and effectively combat them. The MDC cooperates with the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners, e.g. the German Center for Cardiovascular Research (DHZK), and numerous international research institutions. More than 1,600 employees and guests from almost 60 countries work at the MDC; almost 1,300 of them work in science. It is financed 90 percent by the Federal Ministry of Education and Research and 10 percent by the State of Berlin and is a member of the Helmholtz Association of German Research Centers. www.mdc-berlin.de

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LinksOriginal publicationInstitute for Medical Genetics and Human Genetics at CharitéMax Planck Institute for Molecular GeneticsMax Delbrück Center for Molecular Medicine

ContactProf. Dr. Stefan MundlosDirector of the Institute for Medical Genetics and Human GeneticsCharité – Universitätsmedizin BerlinHead of the research group “Development and Disease” Max Planck Institute for Molecular Genetics: +49 30 450 569 122E-mail: stefan.mundlos (at) charite.deDr. Darío LupiáñezHead of the group “Epigenetics and Sex Development” Berlin Institute for Medical Systems Biology (BIMSB) Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) t: +49 30 9406-3085E-Mail: Dario.Lupianez ( at) mdc-berlin.de

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