Jaakko Leinonen's doctoral thesis demonstrates the value of follow-up studies of genetic associations

Jaakko Leinonen’s thesis entitled "Moving beyond GWAS: Exploring the Function of the Gene LIN28B Associated with Pubertal Timing” focuses on exploring the molecular mechanisms by which LIN28B affects puberty. His doctoral dissertation will be publicly examined on 10 October, with the permission of the Faculty of Medicine of the University of Helsinki.

During the past 20 years, researchers have been able to identify tens or even hundreds of associated genetic variants for almost any studied human trait. However, we typically understand rather little about the biology behind these genetic associations. More work focusing on the functional characterization of these findings is thus greatly needed.

M.Sc. Jaakko Leinonen graduated from the University of Helsinki in 2011 with human genetics as his major subject. He started working with his Master’s thesis work at FIMM in the group of Elisabeth Widén in 2010, and started his PhD project in the same group in 2012.  The main aim of his thesis was to characterize the molecular mechanisms by which genetic variants nearby a gene called lin-28 homolog B (LIN28B) associate with pubertal timing.

The topic immediately raised my scientific curiosity since the LIN28B association signal was particularly strong and robust but no information what so ever about the function of the gene existed.

- Jaakko Leinonen

Jaakko’s thesis consists of three first-author publications, one of which is currently under review. In the first sub-study, he utilized Finnish population cohorts and showed that LIN28B associates with variation in several body size parameters in adult humans, although showing little evidence of affecting metabolism.

In the two other publications, zebrafish models played a major role. The fish experiments showed that modulating the amount of ling28b expression during embryogenesis affects the growth patterns of the fish.

It was very rewarding to see that that the effects that LIN28B has on body size seem to be evolutionarily conserved. The effect on zebrafish growth patterns mimicked the human data surprisingly well.

Yet, a critical piece of information came from the gene expression studies. These data showed that the sequence variants associating with pubertal timing affect LIN28B expression mostly in the hypothalamus and the pituitary of adult humans, highlighting the gene’s potential to contribute to sex steroid signaling. UK biobank data on testosterone levels provided further prove for this hypothesis.

Throughout his thesis work, Jaakko has combined data from very different while complementary sources. In addition to utilizing large-scale biobank and gene expression datasets, he has performed extensive laboratory experiments using zebrafish as a model organism. This also means that he has used a notable wide variety of wet-lab and biostatistical methods. He has, for example, performed zebrafish embryo microinjections to transiently dysregulate gene expression and created permanent fish knockouts using the CRISPR-Cas9 technology with the support of the zebrafish core facility of the University of Helsinki.

Overall, the thesis work made substantial progress in understanding the molecular basis of the timing of puberty. Based on the data, regulation of sex steroid signaling might be the most likely mechanism driving many of the LIN28B association signals.

– Given the complexity of the phenotypes we are studying, our strategic decision of using multiple study approaches has turned out to be of huge importance. Otherwise, we would not have been able to show that LIN28B affects the timing and tempo of human growth in an extremely complex way, Jaakko concludes.

FIMM community has greatly benefited from Jaakko’s social and proactive personality. During his thesis project years, he has been an active member of the FIMM PhD Student and Postdoc council and organized several soft skill training sessions and sports activities.

Being able to maintain a healthy work-life balance is also one of Jaakko’s clear strengths: two of his three kids were born during the thesis project. Even if the family is an extremely important counterbalance for the research work, Jaakko pointed out that the upcoming years will also be an interesting observation period for a puberty researcher.

Jaakko has already taken the first steps of his post-doctoral career phase. Since May, he has been working in the group of Academy Research Fellow Taru Tukiainen at FIMM, focusing on studying the genomics of sex differences in different diseases.

The public examination of Jaakko Leinonen’s thesis will take place on 10 October 2019 at 11 am in the lecture hall 2 of Haartman Institute, Haartmaninkatu 3. Professor Alexandre Reymond (Université de Lausanne, Switzerland) will serve as the opponent and Professor Samuli Ripatti as the custos. The dissertation is also available in electronic form and can be downloaded here.