Whole genome sequencing of spermatocytic tumours, a rare testicular tumour at the crossroads between somatic and germline mutational processes.

Seminar Honours Programme

Aïsha Mientjes

aishamientjes@gmail.com

4460960

 

Whole genome sequencing of spermatocytic tumours, a rare testicular tumour at the crossroads between somatic and germline mutational processes.

 

Speaker: Anne Goriely

Department: Molecular Medicine

Subject: Whole genome sequencing of spermatocytic tumours, a rare testicular tumour at the crossroads between somatic and germline mutational processes.

Location: Erasmus MC

Date: 28-06-2017

 

The speaker started of the seminar by explaining the fact that there are not just two types of mutations. Beside germline mutations in an embryo and somatic mutations in an adult, there are also somatic mutations during development (postzygotic mutations) and mutations in the germline of an adult. Dr.Goriely by explaining a little bit about spermatocytic tumors. The classical type is type II, but the one that was discussed in the seminar was type III, a slow-growing large tumour in the testes.

 

The next part of the seminar was about the maternal and the paternal age effect. As men and women age, the chances that their offspring is affected by some kind of disease becomes larger. For women this is well known, however there are also quite a lot of diseases linked to having an older father. In the testes of men, spermatogenesis have to be maintained. In order to do this many cells have to be divided. As the father ages, mutations become more common, leading to defects in the offspring. However, not all mutations show enrichment in sperm as the father ages.

 

The final part of the seminar was about selfish mutations in the testes. Selfish selection is an oncogenic process, which can lead to the formation of tumours. In regions with strong mutations, there is impaired spermatogenesis. The research group of Dr.Goriely also sequenced the DNA of spermatocytic tumours and they found out that these tumours have quite strange patterns and a low mutation rate (compared to other tumours). The take home message was that spermatocytic tumours provide a unique insight into regulative properties of the male germline.

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The image shows a child with apert syndrome, which is a disease associated with the parental age effect.

 

I found it very interesting to hear that the parental age effect is such a major effect in biology. I was aware of the maternal age effect, but I never knew that the age of the father could have such a big impact. I also did not know that selfish mutations affect spermatogenesis. I think that this discovery will definitely have major effects in the future because this research has contributed to a better understanding of the male germline. Hopefully, many syndromes will be treatable in the future because of this. I also believe that this gives major insight into tumour formation. If selfish mutations impair spermatogenesis, they might have similar effects elsewhere in the body. I found the seminar very educational and nice to attend.

 

Molecular and functional heterogeneity in the human haematopoietic stem cell compartment

Speaker: Elisa Laurenti
Department: Cambridge Stem Cell Institute, University of Cambridge, Cambridge
Location: Erasmuc MC Rotterdam
Date: Juni 12, 2017
Author: Teun Huijben

Elisa Laurenti has been interested in stem cells during her entire academic carrier. After doing a PhD and PostDoc in this field, she now has her own lab at Cambridge, where she studies the heterogeneity in the human haematopoietic stem cell (HSC) compartment. In this one hour she introduced us to the field and explained the research she has performed in the last years.

The main point of Elisa’s talk was that where we all think of stem cells as just stem cells, there is actually a large heterogeneity between them. By quantifying the differences between the different HCSs, she hopes to define distinct subsets with different functions, characteristics and detectable markers within the broad HSC-pool.

By single-cell analysis, Elisa found two distinct subsets of haematopoietic stem cells: long-term HSCs (LT-HSC) and short-term HSCs (ST-HSCs). They are characterized by just two surface markers: LT-HSCs express high levels of CDf49 and low levels of CD90, where ST-HSCs have opposite expression levels. The functional difference between them is that LT-HSCs divide very rarely, and ST-HSCs divide more often.

Transcriptional analysis of LT-HSCs and ST-HSCs didn’t give any results, they both showed the same expression landscapes. One explanation for this could be that both cells are very quiescent and therefore not transcriptionally active. The solution Elisa and her colleagues found was to activate the cells and then analyse their transcriptomes. Once activated, the cells start in quiescence, which is a ’sleeping’ state, and are then activated. The ST-HSCs are activated earlier than LT-HSCs, which is another functional difference between them.

To activate the in vitro cultured HSCs, they are transplanted into living mice or into in vitro cultured tissues. Both activated cells are analyzed by single RNA-seq and microarrays. By doing this, they found at least 34 genes that are differently expressed between two subsets. CDK6 appeared to have to most distinct difference in expression between the two groups and was the best gene to indicate whether a cell is ST-HSC or LT-HSC. Surprisingly, treatment with CDK6 determined the state of the cells: over-activation of CDK6 resulted in a faster activation and a CDK6 inhibitor resulted in slower activation.

However, next to this direct effect by changing the expression level of CDK6, also long-term effects were measured. When CDK6 was over-expressed, LT-HSCs gained a positive competitive advantage over SC-HSCs over the long term. In other words, they outnumbered the ST-HSCs. This can be explained by the fact that CDK6 stimulates activation of the cells. ST-HSCs already activate quite fast, so stimulating activation results in activation of all ST-HSC. They all start differentiating and no ST-HSC will be left. LT-HSCs on the other hand, activate more slowly and will remain abundant in the HSC-pool, and will eventually dominate over the ST-HSCs in number.

In the remainder of the time, Elisa told about her current research in further defining subsets of haematopoietic stem cells by finding new markers that characterize distinct groups. Her talk emphasized once more the difficulties we face when looking at stem cells, or molecular biology in general; tissues are very heterogenous and we do not yet know a lot about all their differences. However, her talk was very clear and she is obvious an important person in this field.