Both balanced chromosomal rearrangements and severe loss-of-function mutations are relatively common genetic alterations that can dramatically change or even completely destroy normal gene function. Mapping the exact location of chromosomal rearrangements has proven to be very helpful in identifying disease genes. In the past, cytogenetic techniques such as fluorescent in situ hybridization were used to locate the exact breakpoints while modern sequencing technologies have lately revolutionized this process.
The main aim of M.Sc. Tiia Maria Luukkonen’s thesis entitled "Consequences of Balanced Translocations and Loss-of-function Mutations", was to characterize the molecular and phenotypic consequences of several balanced chromosomal rearrangements utilizing next generation sequencing. Furthermore, she studied the impact of a set of loss-of-function mutations on atopic dermatitis. Tiia will defend her doctoral dissertation in the Faculty of Biological and Environmental Sciences, tomorrow, 3 November 2017.
Tiia graduated from the University of Helsinki in 2010 with human genetics as her major subject. She did her Master’s thesis at the National Institute for Health and Welfare (THL) and started her thesis project under the supervision of late Academician of Science, Leena Peltonen-Palotie and docent Teppo Varilo. Later on Professor Aarno Palotie joined the supervisor team and Tiia became a member of his group at FIMM. The thesis work has thus been done both at FIMM, THL and Department of Medical Genetics, University of Helsinki.
In her thesis work, Tiia has studied two different patient cohorts. Balanced translocation studies were based on Teppo Varilo’s dataset of more than 3000 individuals. This resource contains all known carriers of reciprocal balanced translocations and inversions in Finland. The atopic dermatitis cohort consist of 501 subjects recruited through the Helsinki University Skin and Allergy Hospital.
Tiia’s thesis consists of four publications, one of which is in press and one a manuscript under review. In the first three publications of the thesis, she studied the consequences of balanced translocations in four Finnish families with different but severe symptoms.
In two of the families the breakpoint was shown to locate within a gene, indicating a role of the neurotrimin (NTM) gene in aortic and intracranial aneurysm and the solute carrier family 14 member 2 (SLC14A2) gene in developmental verbal dyspraxia. The two other studied families had distinct vascular phenotypes. Surprisingly, an identical translocation between chromosomes 1 and 12, located outside any putative genes, was seen in both families.
In all these three projects, the most important step was to identify the exact translocation breakpoints using paired end and mate pair next generation sequencing. Our results demonstrate the feasibility of these methods for the identification of candidate genes in patients with potentially disease-associated chromosome rearrangements.
- Tiia Luukkonen
The fourth publication focused on a set of loss-of-function mutations in skin barrier genes. In this collaborative project, Tiia was able to show that certain null mutations in the filaggrin (FLG) gene increase the risk of atopic dermatitis and asthma thus replicating an earlier finding for the first time in the Finnish population. In addition, the results showed that the mutations do not associate with disease severity or treatment response.
Overall, the thesis work made substantial progress in understanding the genetic causes of the symptoms the studied individuals had. In addition to advancing scientific knowledge, this information is very valuable to the families in question.
Balanced chromosomal rearrangements are very heterogeneous and therefore large-scale consortium efforts are needed. Our research group has contributed to this effort by establishing a systematic survey of balanced chromosomal rearrangements in Finns. Our group belongs to the International Breakpoint Mapping Consortium, organized by the Wilhelm Johannsen Centre for Functional Genome Research in Denmark.
Currently samples from 50 Finnish balanced translocation carriers are being sequenced in Denmark and we are expecting to identify novel disease-associated balanced chromosomal rearrangements in the future. I’m very happy to see that research on this unique sample cohort will continue!
In addition to her thesis project, she has also found time to study marketing in the Aalto University and to share her knowledge by teaching human genetics both in Finnish and in English.
Tiia has enjoyed working at FIMM and is grateful for the collaborative and supportive research environment of the Human Genomics programme. During the past few years, she has been very actively involved in organizing many of the activities FIMM has to offer for students and staff, such as the annual retreats and the soft skills training sessions of the PhD and Postdoc council. Her role in creating a pleasant working atmosphere and her optimistic nature are truly appreciated by her fellow students!
Ambitious challenges drive Tiia to do her best also out of working hours: CrossFit community and the competitions both push her to exceed herself and make her feel at home each day.
In the future, Tiia would like to see herself in a position where she could combine her versatile skills and interests. Ideally, this could be something in the interphase of research and industry.
The public examination of Tiia Luukkonen’s thesis will take place on 3 November 2017 at 13 in the Seminar room 1-2 of Biomedicum Helsinki 1, Haartmaninkatu 8. Docent Kirmo Wartiovaara (University of Helsinki) will serve as the opponent and Professor Minna Nyström as the custos.
The dissertation is also available in electronic form and can be downloaded here.